Identification and in silico screening of natural phloroglucinols as potential PI3Kα inhibitors: A computational approach for drug discovery
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Farhan Siddique
,
Ossama Daoui
Abstract
Breast cancer is the biggest cause of death among women worldwide. Natural chemicals from medicinal plants offer promise for cancer therapy. This research screens 29 Dryopteris species plant-derived chemicals, mostly phloroglucinols, for breast cancer therapy potential. First, we used Gaussian09 and DFT/B3LYP/6-311+G(d, p) calculations to evaluate compound stability and reactivity. We conducted molecular docking experiments to identify drugs with high binding affinity for the PI3Kα protein’s active pocket. DJ1–DJ22 were found to be the most effective PI3Kα inhibitors, with energies ranging from −8.0 to −9.2 kJ/mol. From in silico pharmacokinetic and bioactivity screening, DJ3, DJ7, and DJ18 were identified as promising PI3Kα inhibitors. PI3Kα backbone stability was tested in a water model using molecular dynamics simulations employing DJ3, DJ7, DJ18, and Trastuzumab as a pharmacological reference. Synthesis of target-hit DJ3, DJ7, and DJ18 derivatives may lead to breast cancer drug-like molecules for related cancers. The work uses in silico methods to find natural phloroglucinols for breast cancer therapy, enabling new chemotherapeutic drugs.
1 Introduction
Cancer is a prominent cause of mortality in both developed and developing nations [1–3]. According to the American Cancer Society, 2–3% of all fatalities worldwide are attributable to cancer [4]. Cancer develops due to DNA and RNA mutations [5] and improper immune system functioning [6]. Breast cancer is the second most significant cause of cancer-related deaths among women [7,8]. Highly metastatic cancer can instantly spread to other organs, including the brain, lungs, liver, and bones [7]. Over 1.5 million women worldwide are diagnosed with breast cancer each year [7,9]. Analysis of gene expression patterns has shown at least five subtypes of breast cancer with distinct biological characteristics [10,11]. The categorization of breast cancer is determined by the presence or absence of three distinct cell surface receptors: the estrogen receptor (ER), the progesterone receptor, and the human epidermal growth factor (EGF) receptor HER2/neu receptor [12,13]. Approximately 70% of breast cancers are ER-positive breast cancers [14] and react to hormonal treatment therapy or aromatase inhibitors [15]. The mortality rate from breast cancer has not decreased despite the adoption of many targeted therapies [16]. Breast cancer treatments are costly, ineffective, and have severe side effects [17]. It is essential to develop a therapy that is safe, effective, and affordable [17].
For drug discovery and development, natural products have been proven an invaluable source of compounds for diseases such as cancer [18]. An analysis indicated that over 60% of the approved drugs are derived from natural compounds [19]. The National Cancer Institute has reported over 3,000 species of plants with antitumor properties [20,21]. Anticancer chemicals found in terrestrial plants include polyphenols, brassinosteroids, and taxols [22]. Flavonoids, tannins, curcumin, resveratrol, and gallacatechins are polyphenolic chemicals considered anticancer agents [23]. Flavonoids belong to polyphenolic compounds and consist of many secondary metabolites with 10,000 known structures [24]. Flavonoids are believed to reduce cancer risk [25,26]. Vinca alkaloids were the first agents used for cancer [27]. Vinblastine and vincristine were isolated from the Catharanthus roseus G. Don. (Apocynaceae) [28,29]. Another helpful plant medicine, Paclitaxel, has shown promising results in treating ovarian cancer, advanced breast cancer, small cell lung cancer, and non-small cell lung cancer [30]. Semisynthetic derivatives of epipodophyllotoxin, i.e., etoposide and teniposide, are used in treating lymphomas and bronchial and testicular cancers [31,32]. Dryopteris, one of the medicinal plant species [33], also possesses antitumor activity [34] besides anthelmintic [35], antiviral [36], antioxidative [37], and anti-inflammatory activities [33,38]. Primary metabolites in Dryopteris species include phloroglucinols, glycosides, essential amino acids, saponins, mucilage, steroids, and fixed seed oil [26].
Identifying various target proteins has revolutionized cancer therapy by providing potential targets for drug development [17]. These proteins can be potential drug targets and inhibit cancer progression [39]. PR is a crucial ER target gene that has been linked to breast cancer as a lifetime risk factor [40]. p53R2 is another target responsible for repairing DNA damage [41]. Literature-based data [42,43] show that suppressing this protein can suppress the proliferation of breast cancer cells. Among these targets, PI3Kα (phosphoinositide 3-kinase) [44] has gained significant attention due to its crucial role in cell proliferation, survival, and metabolism. PI3Kα is a lipid kinase that catalyzes the conversion of phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3) [45], which activates downstream signaling pathways, such as the AKT/mTOR pathway, leading to cell growth and survival. The PI3Kα pathway is often dysregulated in cancer, with mutations or amplifications in PIK3CA (the gene encoding the catalytic subunit of PI3Kα) commonly found in various cancer types, including breast, ovarian, and lung cancers [46]. Inhibition of PI3Kα can provide a potential therapeutic strategy for these cancers. Several PI3Kα inhibitors have been developed and are currently undergoing clinical trials for cancer treatment [47]. These inhibitors can be broadly classified into three categories based on their selectivity: pan-PI3Kα inhibitors, which target all isoforms of PI3Kα; isoform-specific inhibitors, which target either the p110α or p110δ isoforms of PI3Kα; and dual inhibitors, which target both PI3Kα and mTOR [48]. While PI3Kα inhibition has shown promise as a therapeutic strategy for cancer, it can also cause side effects due to the role of PI3Kα in normal cellular processes [49]. Therefore, there is a need for further research to identify more specific and effective inhibitors and to understand the molecular mechanisms of PI3Kα signaling in cancer progression.
Computational approaches, including computer-aided drug design (CADD), are of utmost importance in identifying and developing anticancer pharmaceuticals [50,51]. Computational techniques are employed to simulate and forecast the interactions between pharmacological molecules and biological targets, facilitating the discovery of potential drug candidates. The aforementioned methodology garnered considerable recognition in the year 1981 and has since resulted in a multitude of key advancements in the field of pharmaceutical exploration [52]. Computational approaches, including structure-based drug design, have been pivotal in discovering several FDA-approved anticancer medications, including Crizotinib and Axitinib [53]. Ligand-based methodologies have been employed in developing pharmaceutical agents that selectively target cancer-associated pathways, such as tubulin inhibitors for regulating the cell cycle and aromatase inhibitors for treating estrogen receptor-positive breast cancer [54]. Despite the considerable advancements made thus far, continuous research is being conducted to strengthen further the use of computational approaches in creating anticancer drugs [55].
Previous studies have investigated PI3Kα inhibitors using computational approaches, mainly from natural products. These studies targeted PI3Kα for specific malignancies [56–60]. The specific involvement of PI3Kα in breast cancer encompasses mutations in the PIK3CA gene, which encodes the PI3Kα subunit, often seen in many subtypes of breast cancer. The presence of these mutations results in the continuous activation of PI3Kα, hence playing a role in the onset and advancement of breast tumors. PI3Kα signaling frequently exhibits hyperactivity in HR+ breast cancer, a substantial subset within the spectrum of breast cancer patients [46]. The aforementioned route can potentially augment resistance to hormone treatments, establishing its significance as a crucial target for therapeutic intervention. In the realm of targeted therapies, explicitly focusing on medicines that target HER2 (e.g., Trastuzumab), the activation of PI3Kα has been seen to contribute to resistance, hence necessitating its inclusion as a crucial factor in breast cancer treatment methods [49].
However, no research has been conducted on identifying kinase inhibitors against PI3Kα using structure-based virtual screening approaches and comparing them with standard drugs. PI3Kα is a kinase enzyme, and kinase inhibitors are used to prevent autophosphorylation of the protein’s tyrosine residues. Therefore, it is essential to discover new kinase inhibitors against PI3Kα using molecular docking and dynamics investigations, compared to traditional anticancer medications, to treat breast cancer. This research gap allows researchers to develop new kinase inhibitors against PI3Kα using structure-based methodologies. The use of molecular docking and dynamics investigations will enable the identification of potential inhibitors and provide insights into the binding mechanism of the inhibitors with the target protein. By comparing the efficacy of the newly discovered inhibitors with standard drugs, we can evaluate their potential for clinical applications in breast cancer treatment. This study will contribute to the development of new and effective treatments for breast cancer and could potentially lead to the discovery of novel PI3Kα inhibitors for other malignancies. In this study, Tamoxifen and Trastuzumab, used as reference molecules alongside PI3K inhibitors, provide a comparative framework to assess the effects and potential therapeutic value of the tested natural compounds on PI3K modulation. It allows researchers to evaluate the compounds’ mechanisms of action, efficacy, and translational potential concerning established drugs used in clinical practice.
The main goal of this study is to identify promising and effective bioactive compounds for breast cancer therapy by screening various phytochemical molecules derived from Dryopteris species. The selection of substances for in silico research was based on several factors, including compound data received by LC-MS, their biological relevance, availability of experimental data, and potential therapeutic value [61,62]. These substances have been shown to interact with specific molecular targets involved in various diseases or biological processes, and their molecular structures have been well-characterized experimentally [63]. Furthermore, we focused on substances that potentially have therapeutic value, either as existing drugs or as candidates for drug development [64]. Marketed standard anticancer drugs were also employed for comparative evaluation. A total of 29 pharmaceutical compounds were screened, and in silico techniques such as density functional theory (DFT) investigations, physiochemical characterization, docking, ADMET studies, and molecular dynamics (MD) simulations were applied to assess their potential as breast cancer therapeutics. The findings of this study have the potential to provide valuable insights into the development of novel and efficient breast cancer therapies.
2 Computational methodology
2.1 DFT studies
In this study, the structures under investigation, as shown in Table S1, were optimized using DFT calculations with the B3-LYP functional, which includes the D3 correction for dispersion and the 6-311+G (d, p) basis sets [65–68]. The electronic properties of the optimized parameters, including the geometric characteristics, frontier molecular orbitals, and global reactivity biological descriptors, were explored [69]. The energy gap, defined as the difference between the energies of the lowest unoccupied molecular orbital (E LUMO) and the highest occupied orbital (E HOMO), was used to relate to the reactivity and electrical conductivity of molecules. Additionally, Koopman’s theorem determined other electronic characteristics such as hardness, softness, chemical potential, and electrophilicity index. The chemical stability and reactivity were correlated with these parameters [70]. The Gaussian09 suite was used for DFT calculations and the Gaussian View 6 utility was used for visualization [71,72].
2.2 Protocols for molecular docking
The interaction between 29 drug ligands (DJ1–DJ29) and the active pocket of the PI3Kα protein (PDB code: 5DXT) with a resolution of 2.25 Å was studied. The PI3Kα protein structure was prepared using the Discovery Studio 2016 [73] client package, which involved the removal of water molecules and non-protein elements, adding polar hydrogens, and optimizing the protein structure via the CHARMm force field. Assigning appropriate polar hydrogen and Kollman charges and saving the file as a pdbqt [9]. The ligands were drawn in chemdraw ultra, energy minimized in chem 3D pro [74], then optimized for better stability by using DFT as discussed in the DFT section above and then by taking ground state optimized structures [75–78] converted into pdbqt file format using the openbabel GUI program. The conversion method was pivotal in accurately depicting ligand conformations throughout the docking procedure. The ligand preparation process involved the use of AutoDockTools-1.5.6 [79]. Autodock4 was used for the structure-based virtual screening, and the ligand drugs were docked independently into each protein’s active site [80]. The ligand–protein interaction analyzer BIOVIA discovery studio visualizer was used for visualization, and the RMSD value and re-docking of the co-crystal ligand were used for validation [81,82]. Acceptance of poses required docking and experimental ligand RMSD values of less than 2.0. Including these specific characteristics was crucial in the computational calculations for docking, as it ensured the accurate parameterization of ligands to interact with the active region of the PI3Kα protein effectively.
2.3 Pharmacokinetic virtual screening
In drug development, analyzing the pharmacokinetics properties of molecules is critical to identify potential drugs that may fail to reach clinical stages or market due to unfavorable ADME-Tox (Absorption, Distribution, Metabolism, and Excretion – Toxicity) characteristics [1]. To solve this puzzle, this research analyzed the molecular structures of 14 drugs and utilized molecular docking modeling to exclude those with unacceptable toxicity concerns. Bioavailability, pharmacokinetics, and molecular toxicity may all be predicted in silico, and there are several web server models available for doing so, such as SwissADME [83], pkCSM, ADMETlab 2.0 [84], OSIRIS Property Explorer [85], and Molinspiration [86]. This work used OSIRIS Property Explorer and Molinspiration platforms to evaluate candidate therapeutic compounds and drug standards for toxicity and physicochemical characteristics. These platforms assessed the candidate drugs’ specific physico-chemical properties and potential toxicity risks.
2.4 Utilizing ligand efficiency (LE), ligand lipophilic efficiency (LLE), and fit quality (FQ) for effective lead selection in drug design
In early drug discovery, researchers juggle the potency and size/complexity of candidate molecules. LE, LLE, and FQ are metrics that help assess these factors (https://doi.org/10.1016/j.ddtec.2010.11.003).
LE relates a ligand’s binding affinity (measured by pIC50 or ΔG) to its size (number of heavy atoms). A higher LE indicates more potent binding per unit size, favoring smaller, more efficient molecules. LE is calculated as
LLE goes beyond size, considering lipophilicity (log P), which is a measure of a molecule’s preference for fatty environments. High log P can lead to non-specific interactions, so LLE aims for strong binding while minimizing reliance on lipophilicity. LLE is calculated as
FQ builds on LE by incorporating a () scaling factor to account for the non-linear relationship between LE and size. Ideally, FQ values close to 1 indicate optimal binding efficiency for a molecule’s size. FQ is calculated as
2.5 MD simulations
MD simulations were performed using the Desmond software [87] package to investigate the dynamical and structural properties of PI3Kα and its filtered complexes, including DJ3, DJ7, DJ18, and Trastuzumab. The simulations were run for 100 ns and were analyzed in terms of root mean square deviation/fluctuation of atomic positions (RMSD and RMSF), protein–ligand interactions, and various structural properties of the ligands [26,76,88]. The protein–ligand systems were generated using the OPLS3e force field and the Maestro 12.8 interface protein preparation wizard [89]. The systems were solvated in an orthorhombic water box using the single point charge (SPC) model, and a physiological salt concentration of 0.15 M. Na+ and Cl− ions were added to neutralize the charge [90,91]. The systems’ energy was optimized using a Columbian interaction with 9 cutoffs and a 0.8 grid phase. To solve the long-range electrostatic interactions, a smooth particle mesh Ewald method was used. The systems were slowly heated to 300 K and a pressure of 1.01325 bar using the Nose-Hoover thermal algorithm and the Martina-Tobias-Klein method. The simulations were run for 100 ns under the set (NPT), and the settings related to system relaxation were set to 1 ps and 2 fs. The resulting simulations provide valuable insights into the dynamics and structural properties of the protein–ligand complexes [91,92]
3 Results and discussion
3.1 Structural analysis of lead molecules using DFT
Table 1 provides several energetic parameters and molecular properties for compounds DJ1–DJ29, as well as two standard drugs (Tamoxifen and Trastuzumab), obtained through DFT calculations at the B3LYP/6-311+G(d, p) level in the gas phase. The optimization energy reflects the stability of a molecule in its lowest-energy conformation. Compounds DJ1–DJ29 exhibited optimization energies ranging from −4411.57 to −641.59 a.u. Lower values indicate more excellent stability, suggesting that DJ1–DJ29 have relatively stable conformations. The dipole moment measures the polarity of a molecule, indicating its potential for intermolecular interactions. Compounds DJ1–DJ29 showed dipole moments ranging from 0.39 Debye to 17.77 Debye. More prominent dipole moments suggest higher polarity, which can contribute to stronger intermolecular interactions. Polarizability quantifies the ease with which an external electric field can distort a molecule’s electron cloud. Compounds DJ1–DJ29 exhibited polarizability values ranging from 145.12 a.u. to 673.24 a.u. Higher polarizability implies a greater ability of the electron cloud to deform in response to external influences. The HOMO and LUMO energies provide insights into the electronic properties and reactivity of the molecules. The HOMO represents the highest occupied molecular orbital, while the LUMO corresponds to the lowest unoccupied molecular orbital. Compounds DJ1–DJ29, and the standard drugs displayed varying HOMO and LUMO energies. The HOMO–LUMO energy gap indicates the energy required for an electron transition from the HOMO to the LUMO. Smaller energy gaps suggest higher reactivity. Compounds DJ1–DJ29 exhibited ∆eV values ranging from 2.63 to 8.95 eV, indicating variations in their reactivity levels.
Energetic parameters for compounds DJ1–DJ29 and standard drugs using the DFT/B3LYP/6-311+G(d, p) level in the gas phase
| Ligand | Optimization energy (a.u.) | Dipole moment (Debye) | Polarizability (a.u.) | HOMO (eV) | LUMO (eV) | HOMO–LUMO (
|
|---|---|---|---|---|---|---|
| DJ1 | −1456.32 | 8.85 | 303.29 | −5.72 | −1.90 | 3.82 |
| DJ2 | −728.75 | 1.21 | 145.64 | −6.36 | −0.76 | 5.59 |
| DJ3 | −1495.63 | 6.49 | 307.54 | −6.48 | −2.35 | 4.13 |
| DJ4 | −1416.98 | 7.83 | 281.74 | −6.43 | 2.53 | 8.95 |
| DJ5 | −1416.96 | 6.57 | 286.49 | −6.18 | −1.99 | 4.19 |
| DJ6 | −1495.62 | 4.67 | 289.62 | −6.22 | −1.95 | 4.27 |
| DJ7 | −1574.27 | 2.98 | 336.04 | −6.20 | −1.92 | 4.28 |
| DJ8 | −2144.54 | 9.93 | 437.68 | −5.96 | −2.43 | 3.53 |
| DJ9 | −2183.88 | 3.67 | 435.93 | −6.03 | −2.50 | 3.53 |
| DJ10 | −2223.20 | 7.36 | 451.19 | −5.93 | −2.37 | 3.56 |
| DJ11 | −1495.62 | 7.76 | 298.78 | −6.50 | −2.21 | 4.30 |
| DJ12 | −1456.31 | 5.39 | 298.01 | −6.02 | −2.38 | 3.64 |
| DJ13 | −1534.96 | 5.65 | 327.60 | −6.03 | −1.92 | 4.11 |
| DJ14 | −1416.98 | 3.95 | 285.62 | −6.20 | 1.92 | 8.13 |
| DJ15 | −1342.90 | 10.98 | 277.52 | −6.07 | −2.81 | 3.26 |
| DJ16 | −2262.55 | 13.36 | 472.69 | −5.50 | −2.87 | 2.63 |
| DJ17 | −2262.51 | 5.61 | 456.44 | −5.73 | −2.46 | 3.27 |
| DJ18 | −641.59 | 1.60 | 145.12 | −7.05 | −1.85 | 5.21 |
| DJ19 | −2301.86 | 4.09 | 478.80 | −6.01 | −2.28 | 3.73 |
| DJ20 | −2264.89 | 13.65 | 456.55 | −6.13 | −2.40 | 3.73 |
| DJ21 | −2186.21 | 13.97 | 445.86 | −6.26 | −2.13 | 4.13 |
| DJ22 | −2301.83 | 4.96 | 479.11 | −5.77 | −2.25 | 3.52 |
| DJ23 | −2873.27 | 9.91 | 568.93 | −5.77 | −2.44 | 3.34 |
| DJ24 | −2992.46 | 6.45 | 586.85 | −6.19 | −2.28 | 3.91 |
| DJ25 | −1534.95 | 8.41 | 323.83 | −5.79 | −2.02 | 3.78 |
| DJ26 | −2872.09 | 0.39 | 576.33 | −6.14 | −2.52 | 3.61 |
| DJ27 | −1344.10 | 7.12 | 273.36 | −5.76 | −2.41 | 3.34 |
| DJ28 | −4411.57 | 17.77 | 586.99 | −6.97 | −2.60 | 4.36 |
| DJ29 | −3030.60 | 12.30 | 615.47 | −5.70 | −2.44 | 3.26 |
| Tamoxifen | −1138.53 | 1.44 | 333.76 | −5.54 | −1.11 | 4.43 |
| Trastuzumab | −3264.51 | 12.94 | 673.24 | −6.27 | −2.91 | 3.37 |
The results showed that compounds DJ16, DJ18, and DJ28 displayed larger dipole moments, indicating their higher polarity and potential for intermolecular interactions compared to other compounds. On the other hand, compounds DJ7, DJ15, DJ17, and DJ26 exhibited higher polarizability values, suggesting their greater ability to deform in response to external electric fields. Regarding the HOMO–LUMO energy gaps, compounds DJ4, DJ14, and DJ16 showed larger values, indicating relatively lower reactivity than other compounds. Conversely, compounds DJ2, DJ5, DJ6, DJ9, DJ18, and DJ26 had smaller energy gaps, suggesting higher reactivity and potential for chemical transformations. HOMO–LUMO for the finally filtered compounds are also plotted in Figure 1.
The HOMO and LUMO contour maps for the substances under study. The HOMO–LUMO energy gap is shown as a double arrow.
Table 2 presents the physiochemical properties and quantum chemical descriptors of 29 compounds (DJ1–DJ29) along with two standard drugs, Tamoxifen and Trastuzumab, calculated using the DFT/B3LYP/6-311+G(d, p) level in the gas phase. The chemical hardness (η) indicates the resistance of a molecule to chemical reactions – the values of η range from 1.31 to 4.48 eV for the compounds studied. Among them, DJ16 has the lowest hardness value of 1.31 eV, indicating its high reactivity towards chemical reactions. On the other hand, DJ4 has the highest hardness value of 4.48 eV, suggesting its high stability and low reactivity towards chemical reactions. Tamoxifen and Trastuzumab have hardness values of 2.22 and 1.68 eV, respectively, indicating intermediate reactivity values. The electronegativity (χ) was also calculated to give information on the tendency of a molecule to attract electrons – the values of χ range from 1.95 to 4.79 eV for the compounds studied. DJ4 has the lowest electronegativity value of 1.95 eV, indicating its low tendency to attract electrons. DJ28 has the highest electronegativity value of 4.79 eV, suggesting its high tendency to attract electrons. Tamoxifen and Trastuzumab have electronegativity values of 4.43 and 3.37 eV, respectively, indicating their intermediate tendency to attract electrons. Chemical softness (ζ) tells information about the ease with which a molecule can undergo deformation – the values of ζ range from 0.66 to 2.24 eV for the compounds studied. DJ16 has the lowest softness value of 0.66 eV, indicating its high deformability, while DJ4 has the highest softness value of 2.24 eV, suggesting its low deformability. Tamoxifen and Trastuzumab have softness values of 1.11 and 0.84 eV, respectively, indicating intermediate deformability values. Chemical potential (μ) is a parameter that reflects the tendency of a molecule to donate or accept electrons. The importance of μ ranges from −4.79 to −1.95 eV for the compounds studied. DJ28 has the lowest chemical potential value of −4.79 eV, indicating its high tendency to accept electrons.
Physiochemical properties and quantum chemical descriptors for compounds DJ1–J29 and standard drugs using the DFT/B3LYP/6-311+G(d, p) level in the gas phase
| Ligand | Chemical hardness (η) (eV) | Chemical softness (ζ) (eV) | Electro-negativity (χ) (eV) | Chemical potential (μ) (eV) | Electrophilicity index (ω) |
|---|---|---|---|---|---|
| DJ1 | 1.91 | 0.95 | 3.81 | −3.81 | 13.86 |
| DJ2 | 2.80 | 1.40 | 3.56 | −3.56 | 17.72 |
| DJ3 | 2.06 | 1.03 | 4.42 | −4.42 | 20.17 |
| DJ4 | 4.48 | 2.24 | 1.95 | −1.95 | 8.51 |
| DJ5 | 2.09 | 1.05 | 4.09 | −4.09 | 17.51 |
| DJ6 | 2.13 | 1.07 | 4.08 | −4.08 | 17.77 |
| DJ7 | 2.14 | 1.07 | 4.06 | −4.06 | 17.64 |
| DJ8 | 1.77 | 0.88 | 4.19 | −4.19 | 15.50 |
| DJ9 | 1.76 | 0.88 | 4.27 | −4.27 | 16.07 |
| DJ10 | 1.78 | 0.89 | 4.15 | −4.15 | 15.32 |
| DJ11 | 2.15 | 1.07 | 4.35 | −4.35 | 20.32 |
| DJ12 | 1.82 | 0.91 | 4.20 | −4.20 | 16.04 |
| DJ13 | 2.05 | 1.03 | 3.98 | −3.98 | 16.27 |
| DJ14 | 4.06 | 2.03 | 2.14 | −2.14 | 9.31 |
| DJ15 | 1.63 | 0.82 | 4.44 | −4.44 | 16.07 |
| DJ16 | 1.31 | 0.66 | 4.18 | −4.18 | 11.47 |
| DJ17 | 1.63 | 0.82 | 4.09 | −4.09 | 13.66 |
| DJ18 | 2.60 | 1.30 | 4.45 | −4.45 | 25.77 |
| DJ19 | 1.86 | 0.93 | 4.15 | −4.15 | 16.05 |
| DJ20 | 1.87 | 0.93 | 4.26 | −4.26 | 16.93 |
| DJ21 | 2.06 | 1.03 | 4.19 | −4.19 | 18.11 |
| DJ22 | 1.76 | 0.88 | 4.01 | −4.01 | 14.14 |
| DJ23 | 1.67 | 0.83 | 4.11 | −4.11 | 14.10 |
| DJ24 | 1.95 | 0.98 | 4.23 | −4.23 | 17.49 |
| DJ25 | 1.89 | 0.94 | 3.91 | −3.91 | 14.44 |
| DJ26 | 1.81 | 0.90 | 4.33 | −4.33 | 16.94 |
| DJ27 | 1.67 | 0.84 | 4.09 | −4.09 | 13.98 |
| DJ28 | 2.18 | 1.09 | 4.79 | −4.79 | 25.02 |
| DJ29 | 1.63 | 0.81 | 4.07 | −4.07 | 13.50 |
| Tamoxifen | 2.22 | 1.11 | 4.43 | −4.43 | 21.75 |
| Trastuzumab | 1.68 | 0.84 | 3.37 | −3.37 | 9.54 |
In comparison, DJ4 has the highest chemical potential value of −1.95 eV, suggesting its high tendency to donate electrons. Tamoxifen and Trastuzumab have chemical potential values of −4.43 and −3.37 eV, respectively, indicating intermediate electron donation and acceptance values. Finally, the electrophilicity index (ω) is a parameter that reflects the reactivity of a molecule towards an electrophile – the values of ω range from 8.51 to 25.77 eV for the compounds studied. DJ4 has the lowest electrophilicity index value of 8.51 eV, indicating its low reactivity toward an electrophile. In comparison, DJ18 has the highest electrophilicity index value of 25.77 eV, suggesting its high reactivity toward an electrophile. Tamoxifen and Trastuzumab have electrophilicity index values of 21.75 and 9.54 eV, respectively, indicating intermediate reactivity toward an electrophile.
The molecular electrostatic potential (MEP) is a valuable tool for identifying electrophilic and nucleophilic regions in a molecule. The MEP surface of a compound shows the distribution of electrostatic charges over the surface of the molecule, indicating the regions where electrons are most likely to be found or lost. In this study, the MEP investigations have identified several compounds, including and plotted finally filtered DJ03, DJ07, DJ18, Tamoxifen, and Trastuzumab, with negative regions in their MEP surfaces, as shown in Figure 2. These negative regions are indicative of the presence of nucleophilic sites in these compounds, which can attract electrophiles during chemical reactions. Therefore, the fact of negative regions in the MEP surfaces of these compounds suggests that they have the potential to act as reactive sites and undergo chemical reactions with electrophiles.
MEP surface map for the investigated series of compounds.
In conclusion, the DFT calculations provide valuable information about the energetic parameters and molecular properties of compounds DJ1 to DJ29 and the standard drugs. These results offer insights into their stability, polarity, polarizability, electronic characteristics, and reactivity. Such information is crucial for understanding these compounds’ structural and electronic properties, enabling further exploration of their potential applications in various fields. This study could be significant in designing new compounds or optimizing existing ones for specific purposes, such as drug development. By identifying the regions with the most potential for attachment and attracting electrophiles, researchers can optimize the design of compounds to improve their efficacy and specificity.
3.2 Virtual analysis of ligand–protein affinity
PI3K type 1 inhibitors targeting the PI3Kα isoform have garnered considerable interest for their possible utility in cancer treatment, particularly breast cancer. This research aims to assess the selectivity of potential pharmacological agents for blocking this difficult isoform. Molecular docking simulations are employed to assess the selective affinity of ligands for the PI3Kα target protein, given the crucial role of docking molecules in drug design and evaluation of their possible interactions with biological targets such as proteins. To ensure the reliability of our results, we validate the molecular docking procedure by simulating molecular re-docking [75,76].
3.2.1 Reliability of molecular docking simulations
This study focuses on the analysis of the PI3Kα protein’s structure when bound to the inhibitor GDC-0326 (2s)-2-(2-[1-(propan-2-Yl)-1h-1,2,4-triazol-5-Yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-Yloxy) propanamide) in its crystalline form. The goal is to build a computational benchmark for validation of the molecular docking screening technique. The quality of molecular docking screening is critical for the success of drug design, and it is essential to validate the procedure’s reliability through the simulation of molecular re-docking. By examining the PI3Kα protein in complex with GDC-0326, we aim to provide a reliable and validated benchmark for future computational studies in drug design (Figure 3).
PI3Kα and GDC-0326 in crystal conformation (PDB ID: 5DXT).
Superimposable conformational modes of the original and re-docked GDC-0326 ligand were used to determine the RMSD parameter, which was then used to assess the docking simulation’s efficacy using the online DockRMSD tool (https://zhanggroup.org/DockRMSD/). According to experts, the molecular docking approach is safe and practical when the RMSD value is less than 2 Å for formulating insights into the protein–ligand interactions [93]. As shown in Figure 3, the reference inhibitor GDC-0326 interacts with the PI3Kα protein’s active pocket via hydrophobic, electrostatic, and hydrogen bonding interactions having a number of different active amino acids, including Met772, Pro778, Gln589, Ser854, Val851, Ile932, Met922, Ile848, Ile800, Tyr836, and Asp933. Therefore, it can be inferred that the proposed ligands’ interaction with these amino acids plays an intermediate role in inhibiting PI3Kα enzymatic activity. Using these data and the AutodockVina techniques outlined in our earlier work [75–78], we re-docked GDC-0326 back into the active pocket of the PI3Kα protein and repeated the virtual screening process. The X, Y, and Z grid box distances were all set at 0.375 Å and dimensions of 40 × 40 × 40 Å3 [93], and how well molecules dock together was found to be reliable and feasible.
3.2.2 Molecular re-docking simulation outputs
The results presented in Figure 4 demonstrate the effectiveness of our molecular re-docking simulations, as evidenced by the close agreement between the original and re-docked conformations of the GDC-0326 inhibitor.
Placement of original conformation of GDC-0326 in black and re-docked conformation in green within the active pocket of PI3Kα (a). Re-docked interactions of GDC-0326 toward the reference binding site in 2D (b).
The green re-docked conformation, with a binding energy of −12.0 kcal/mol and an RMSD value of 0.195 Å, closely resembles the original crystal conformation. The similarity between the two conformations indicates that our simulation protocol accurately predicted the interactions between the GDC-0326 inhibitor and the active binding site of the PI3Kα protein. These findings support using our validated PI3Kα protein template for subsequent molecular docking procedures in this study.
3.2.3 Ligand–PI3KAα binding affinities
Following validation of the PI3Kα protein model, we assessed the binding ability of the DJ1–DJ29 ligands to the active binding domain of the protein. The docked conformations with the most negative binding energies were selected for further analysis. The outcomes shown in Table 3 denote that all docked ligands had negative binding energies, demonstrating the suitability of molecular docking for identifying potential drug inhibitors targeting the PI3Kα protein for breast cancer treatment. To provide a context for evaluating candidate inhibitors, we compared the results to commonly used breast cancer chemotherapy drugs, including Paclitaxel, Tamoxifen, and Trastuzumab (PubChem CID: 36314, 2733526, and 146160902, respectively) [94–96].
Most stable docked ligands and their binding energies (for the full list of all 29 compounds and their binding energies, refer to Table S2)
| Ligand identification | Docking score (kcal/mol) | Ligand identification | Docking score (kcal/mol) | Ligand identification | Docking score (kcal/mol) |
|---|---|---|---|---|---|
| DJ1 | −7.9 | DJ8 | −7.9 | DJ19 | −8.1 |
| DJ3 | −8.1 | DJ11 | −8.7 | DJ20 | −8.2 |
| DJ5 | −8.1 | DJ12 | −8.2 | DJ21 | −8.4 |
| DJ6 | −7.9 | DJ13 | −8.3 | DJ22 | −9.2 |
| DJ7 | −8.5 | DJ18 | −7.9 | ||
| Standard drug (Trastuzumab) | −8.3 | Standard drug (Tamoxifen) | −7.9 | Standard drug (Paclitaxel) | 16.0 |
Table 3 shows the binding energy scores for the most stable docked ligands, as evaluated by the molecular docking simulations. Table 3 lists the names of the most stable 14 ligands (DJ1–DJ22) and their corresponding binding energies in kcal/mol. A lower binding energy indicates a more stable binding interaction between the ligand and the protein. In comparing the stable docked ligands listed in Table 3, we can observe variations in their docking scores, which provide insights into their predicted binding strengths to the target molecule. Among the ligands with a docking score of −7.9, DJ1, DJ6, DJ8, and DJ18 demonstrate similar affinities toward the target. These compounds are expected to exhibit moderate binding interactions. DJ3 and DJ5, with docking scores of −8.1, display slightly stronger binding affinities than the previous group. DJ7, with a docking score of −8.5, demonstrates a higher affinity toward the target compared to the previous ligands, indicating a potentially stronger binding interaction. DJ11 and DJ13 exhibit docking scores of −8.7 and −8.3, respectively, suggesting they may have even stronger binding affinities toward the target. DJ12 has a docking score of −8.2, indicating a moderate binding strength similar to the ligands with a score of −7.9. DJ19, DJ20, DJ21, and DJ22 exhibit docking scores of −8.1, −8.2, −8.4, and −9.2, respectively. These ligands display relatively strong binding affinities toward the target, with DJ22 having the highest predicted binding strength among all the listed compounds. It is important to note that the standard drugs, Trastuzumab and Tamoxifen, exhibit docking scores of −8.3 and −7.9, respectively, comparable to the ligands with a score of −7.9. However, the standard drug Paclitaxel stands out with a significantly higher docking score of 16.0, suggesting a strong binding affinity towards the target. These observations provide valuable insights into the tested ligands’ potential binding interactions and relative affinities, aiding in the selection and prioritization of compounds for further experimental validation and drug development efforts. Detailed information on the binding energies of all 29 compounds tested, including the ligand conformations and their predicted interactions with the PI3Kα protein, is shown in Table S2.
3.3 In silico pharmacokinetic screening
The binding energies of the 14 molecular structures tested in this study for their ability to bind to PI3Kα ranged from −7.8 to −9.2 kcal/mol, indicating that they have the potential to act as inhibitors of the protein’s activity (Figure 5). However, identifying these structures as lead agents for medicinal use requires further investigation to ensure their suitability as drug candidates. In drug development, it is essential to evaluate not only the binding affinity of a compound to its target protein but also its pharmacological properties, including its efficacy, selectivity, toxicity, and bioavailability. Therefore, further studies are needed to determine the pharmacokinetic and pharmacodynamic properties of the identified lead agents and their potential adverse effects before they can be considered for clinical use as therapeutic agents.
3.3.1 Osiris computations for the selected DJ compounds and standard drugs
Table 4 shows the results of an OSIRIS analysis, a tool used to evaluate the examined molecules’ potential toxicity risks and drug-likeness. The analysis considers several physicochemical properties necessary for predicting a drug candidate’s safety and efficacy. For example, the Drug-score and Druglikeness values indicate how well the molecule fits the characteristics of a drug, such as solubility, bioavailability, and target specificity. The TPSA and Molweight values provide information about the size and polarity of the molecule, which can affect its absorption and distribution in the body. The analysis also evaluates the potential toxicity risks of the molecules, which include reproductive, irritant, tumorigenic, and mutagenic effects. These effects can be caused by the molecule’s chemical structure or physicochemical properties. Based on the results presented in Table 4, some of the molecules, including DJ1, DJ5, DJ6, DJ8, DJ11, DJ12, DJ13, DJ21, and the reference standard Tamoxifen, show potential toxicity risks. In contrast, others DJ3, DJ7, DJ18, DJ19, DJ20, DJ22, and the reference standard Trastuzumab appear to have more favorable drug-like properties and lower toxicity risks. The OSIRIS analysis is useful in screening drug candidates and identifying those with potential toxicity risks, which can then be excluded from further consideration. This helps to ensure that only safe and effective drug candidates are advanced to preclinical and clinical studies.
Results of OSIRIS property explorer evaluations for the examined molecules
| Compound | Drug-like property indicators | Toxicity potential or risks | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Drug-score | Drug like-ness | TPSA (Å2) | Molecular weight (g/mol) | Solubility | cLog P | Reproductive effect | Irritant | Tumorigenic | Mutagenic | |
| DJ1 | 0.300 | −1.910 | 156 | 418 | −4.420 | 3.190 | ± | — | — | — |
| DJ3 | 0.460 | −1.500 | 137 | 432 | −3.200 | 1.320 | − | — | — | — |
| DJ5 | 0.250 | −3.690 | 135 | 404 | −3.270 | 1.360 | + | — | — | — |
| DJ6 | 0.220 | −5.390 | 135 | 432 | −3.810 | 2.270 | + | — | — | — |
| DJ7 | 0.320 | −4.150 | 135 | 460 | −4.350 | 3.180 | − | — | — | — |
| DJ8 | 0.150 | −5.560 | 214 | 612 | −4.360 | 1.900 | + | — | — | — |
| DJ11 | 0.300 | −3.180 | 146 | 432 | −3.770 | 2.450 | ± | — | — | — |
| DJ12 | 0.230 | −5.560 | 146 | 418 | −3.500 | 2.000 | + | — | — | — |
| DJ13 | 0.270 | −4.320 | 146 | 446 | −4.040 | 2.910 | ± | — | — | — |
| DJ18 | 0.420 | −5.530 | 17 | 194 | −3.660 | 3.100 | − | — | — | — |
| DJ19 | 0.180 | −4.320 | 214 | 668 | −5.440 | 3.720 | — | — | — | — |
| DJ20 | 0.190 | −5.080 | 221 | 658 | −5.160 | 3.100 | — | — | — | — |
| DJ21 | 0.140 | −6.330 | 221 | 630 | −4.620 | 2.190 | + | — | — | — |
| DJ22 | 0.130 | −4.150 | 213 | 668 | −6.400 | 4.740 | − | — | — | — |
| #Tamoxifen | 0.350 | 6.300 | 12 | 371 | −4.400 | 4.720 | + | — | — | — |
| #Trastuzumab | 0.690 | 4.680 | 129 | 493 | −3.440 | 0.800 | − | — | — | — |
DJ(XX): Compounds were selected based on color (green = safe, orange = somewhat toxic, and red = extremely toxic); Standard drug representations (#), (+) very toxic; (−) not toxic; (±) moderately toxic.
3.3.2 Molinspiration analysis of filtered DJ compounds and standard drug
Trastuzumab and six other compounds (DJ3, DJ7, DJ18, DJ19, DJ20, DJ22) were tested for their predicted bioactivity toward the PI3Kα target enzyme using Molinspiration calculations. The assay also determined the potential bioactivity in suppressing the target protein’s enzymatic activity based on the number of expected deviations (Nviolations). The compounds that made it through Osiris calculations and were tested with Trastuzumab are summarized in Table 4, along with the findings of Molinspiration predictions.
Table 5 displays the bioactivity scores for the examined molecules, where a score ≠ of 0 suggests a high potential for inhibiting PI3Kα enzymatic activity. The identified violations in D19, D20, and D22 compounds may adversely impact their bioactivity and lead to drug resistance, resulting in their exclusion from further screening for medicinal use in breast cancer treatment. Conversely, DJ3, DJ7, and DJ18 showed the most promising results in binding to PI3Kα and inhibiting its enzymatic activity, making them the most effective lead agents for further rational screening.
A summary of Molinspiration calculations for the examined compounds
| Drug targets | Target protein receptor | Category of bioactivity | Molinspiration bioactivity score | N violations |
|---|---|---|---|---|
| Favorable (F)/unfavorable (UF) | Should be ≠0 | Should be <2 | ||
| DJ3 | PI3Kα ID: 5DXT (enzyme inhibitor) | F | 0.12 | 0 |
| DJ7 | F | 0.23 | 0 | |
| DJ18 | F | −0.35 | 0 | |
| DJ19 | UF | −0.53 | 2 | |
| DJ20 | UF | −0.36 | 2 | |
| DJ22 | UF | −0.49 | 2 | |
| Standard drug (Trastuzumab) | F | 0.80 | 0 |
Docking poses of four ligands DJ3, DJ7, DJ18, and Trastuzumab in PI3Kα active site.
3.4 Investigation of affinity between filtered drugs and proteins
Using the results from pharmacokinetic screening results, we performed an in-depth analysis of the interactions between the filtered drug ligands, including DJ3 (−8.1 kcal/mol), DJ7 (−8.5 kcal/mol), DJ18 (−7.9 kcal/mol), and standard reference drug Trastuzumab (−8.0 kcal/mol), with the active pocket of the PI3Kα enzyme. To gain insights into the conformational behavior of the new drug candidates compared to the standard drug Trastuzumab, we employed 3D and 2D spatial visualizations presented in Figure 6. Additionally, a comprehensive summary of the most noteworthy non-covalent interactions between the filtered ligands and active amino acid residues in the PI3Kα pocket (PDB ID: 5DXT) is provided in Table 5.
Protein–ligand 2D interactions in the PI3Kα–DJ3, PI3Kα–DJ7, PI3Kα–DJ18, and PI3Kα–Trastuzumab complexes.
The lead molecules (DJ3, DJ7, DJ18) and Trastuzumab fit well into the active pocket of PI3Kα based on Figure 6. The interaction analysis in Table 6 indicates that these compounds can interact with most of the important amino acid residues in the active site, such as Gln859, Ser854, Met922, Val850, Ile932, Tyr836, Ile800, Glu849, TRP780, Met772, Pro778, and Ile848. Therefore, these compounds have the potential to inhibit PI3Kα enzymatic activity and may have therapeutic benefits for breast cancer treatment.
Lead compound interactions with PI3Kα
| Ligands with 4E7Y | Hydrogen-binding interaction, residue (distance in Å) | Hydrophobic interaction, residue (distance in Å) | Electrostatic interaction, residue (distance in Å) |
|---|---|---|---|
| PI3Kα-DJ3 | ARG770(2.11,2.62) | TYR836(3.96), MET772(3.60, 4.60), ILE932(4.86, 4.96), PRO778(4.97), ILE800(4.17), VAL851(4.71) | HIS855(4.71) |
| PI3Kα-DJ7 | MET772(3.95), TYR836(3.83), ILE932(4.64, 4.94), MET772(4.94, 4.11), PRO77(4.84), VAL851(4.29) | TRP780(4.92) | |
| PI3Kα-DJ18 | — | ILE932(3.84), TYR836(3.61), VAL851(4.38), PHE930(5.42), TRP780(4.88, 4.94), VAL850(4.95) | — |
| PI3Kα–Trastuzumab | SER774(2.44), VAL851(2.02), GLN859(2.55) | ILE800(5.46), MET922(5.29), ILE932(4.12, 4.23), ILE848(4.96), MET922(3.98) | MET922(3.96) GLU849(2.91), VAL850(3.62), ARG770(4.22 Å), TRP780(5.20, 5.03) |
Reference amino acids (Gln589, Met922, Val850, Ile932, Ile848, Tyr836, Ile800, Pro778, Ser854, Val851, Glu849, Asp933, and Met772).
The lead molecules (DJ3, DJ7, and DJ18) mainly interacted with the reference amino acids through weak conventional hydrogen bonding and hydrophobic interactions. On the other hand, Trastuzumab showed similar types of interactions as predicted for the lead candidates but with the addition of strong electrostatic, halogen, and π-sulfur interactions. However, weak drug interactions are generally more effective in achieving therapeutic goals by targeting protein receptors. Hence, the proposed lead molecules (DJ3, DJ7, and DJ18) may be more appropriate for targeting the PI3Kα enzyme and accomplishing the desired therapeutic outcome than Trastuzumab.
On the other hand, based on the compound efficacy parameters presented in Table 7, there is a strong case to be made that DJ3, DJ7, and DJ18 have structures suitable for further drug design targeting the DJ3 receptor. Here is a breakdown of the parameters and how they support this claim:
Strength and size/complexity endpoints of candidate compounds for early drug design in terms of ligand efficacy (LE), lipophilic ligand efficacy (LLE), and FQ
| Ligand | Docking experiments | Parameter | ||||||
|---|---|---|---|---|---|---|---|---|
| Binding energies (kcal/mol) |
|
|
HA | cLog P | LE | LLE | FQ | |
| Recommended range for hits to lead [2] | >−6 | − | <100 | — | — | LE ≥ 0.3 | LLE ≥ 3 | FQ ≥ 0.8 |
| DJ3 | −8.1 | 8.1 | 1.14 | 31 | 1.320 | 0.26 | 6.78 | 0.732 |
| DJ7 | −8.5 | 8.5 | 0.58 | 33 | 3.180 | 0.25 | 5.32 | 0.735 |
| DJ18 | −7.9 | 7.9 | 1.60 | 14 | 3.100 | 0.56 | 4.80 | 1.245 |
| Trastuzumab | −7.9 | 7.9 | 1.60 | 16 | 0.800 | 0.50 | 7.10 | 1.344 |
LE: This metric evaluates binding affinity per unit size of the molecule. DJ18 has the highest LE (0.56) compared to both Trastuzumab (0.50) and the other DJ3 ligands (0.25–0.26). This suggests that DJ18 might achieve good potency with a smaller, potentially more drug-like structure.
Lipophilic ligand efficiency (LLE): This parameter considers both potency and lipophilicity (preference for fat). While Trastuzumab has the highest LLE (7.10), all DJ3 ligands exhibit good values (4.80–6.78). This indicates a favorable balance between potency and lipophilicity, potentially leading to good absorption and distribution properties.
FQ: This metric normalizes LE for size, allowing for a size-independent assessment of efficient binding. Interestingly, DJ18 again stands out with the highest FQ (1.245) exceedingly even Trastuzumab (1.344). This suggests DJ18 might have a near-optimal fit within the binding pocket of the DJ3 receptor. However, all DJ3 ligands have FQ values above 0.7, indicating a generally good fit.
Overall, while Trastuzumab has a slightly higher LLE and FQ, DJ3 ligands, particularly DJ18, show promising potential for drug design. DJ18 exhibits high LE and FQ, suggesting efficient binding and a good fit within the target receptor. Additionally, all DJ3 ligands have good LLE values, indicating a potential balance between potency and favorable drug-like properties.
3.5 Molecular dynamics analysis (MDA)
To verify the accuracy of our findings, we assess the conformational stability of Trastuzumab and the ligands DJ3, DJ7, and DJ18 in the active pocket of the PI3Kα enzyme (PDB ID:5DXT). For this purpose, we employ MD simulation techniques to generate predictions about the stability of the PI3Kα backbone in its complex form with the analyzed ligands, including DJ3, DJ7, DJ18, and standard drug Trastuzumab, within an aqueous system.
3.5.1 RMSD and RMSF analysis
The RMSD trajectory analysis of the PI3Kα protein structure, when complexed with Trastuzumab and ligands DJ3, DJ7, and DJ18, indicates a stable structural equilibrium, as the RMSD values remain below the 4 Å threshold (as shown in Figure 7a). This stability is due to the close RMSD values observed in all analyzed complexes, with the average RMSD values for PI3Kα-DJ3, PI3Kα-DJ7, PI3Kα-DJ18, and PI3KAα- Trastuzumab being 2.59, 2.75, 2.55, and 2.80 Å, respectively. Furthermore, the RMSF analysis of the amino acid residues in the PI3KAα side chain shows insignificant fluctuations over 100 ns of MD, as depicted in Figure 7b. The average RMSF variations observed in the PI3Kα-DJ3, PI3Kα-DJ7, PI3Kα-DJ18, and PI3Kα- Trastuzumab complexes are 1.21, 1.26, 1.14, and 1.23 Å, respectively. The observation of amino acid fluctuations exceeding 5 Å in the range of 150–250 in the PI3Kα–DJ3, PI3Kα–DJ7, PI3Kα–DJ18, and PI3Kα–Trastuzumab complexes, as depicted in Figure 7b, signifies significant structural dynamics within these complexes. Such fluctuations are indicative of regions within the protein complexes that undergo notable conformational changes or flexibility. In the context of protein–ligand or protein–antibody interactions, these fluctuations could be attributed to dynamic adjustments in the binding interface. Flexible regions within the protein complexes may undergo conformational changes upon ligand or antibody binding, enabling optimal molecular recognition and stabilization of the complex. Understanding these dynamic fluctuations is crucial for elucidating the mechanisms of interaction between the proteins and their ligands or antibodies. It sheds light on how these complexes achieve specificity and affinity in their binding interactions. Moreover, these dynamic regions can serve as potential targets for structure-based drug design or antibody engineering to enhance binding affinity or modulate protein function. Overall, the observation of significant amino acid fluctuations in the 150–250 range in the studied protein complexes highlights the dynamic nature of these interactions and provides valuable insights into their molecular mechanisms. Additionally, when analyzing the RMSF values of the ligands within the PI3Kα pocket, we observed several deviations, but none exceeding 5 Å over the 100 ns simulation (as shown in Figure 7c). The ligands DJ3, DJ7, DJ18, and Trastuzumab displayed average RMSF fluctuations of 1.36, 2.95, 3.45, and 0.96 Å, respectively.
PI3Kα Protein-ligands during 100 ns MD simulation. (a) RMSD, (b) Residues of Proteins interacting, and (c) RMSF.
3.5.2 Protein–ligand interactions
Figures 6–9 illustrate the specific interactions between the ligands DJ3, DJ7, DJ18, and Trastuzumab, respectively, and the active amino acid residues located within the pocket of the PI3Kα protein. The figures provide a detailed representation of the interactions between the ligands and the protein residues over the course of the 100 ns simulation. The trajectory data obtained from the simulation are used to visualize the interactions that persist between the ligands and the active amino acid residues within the protein pocket during the entire simulation time, ranging from 0.00 to 100.00 ns. These figures provide a comprehensive understanding of the nature and stability of the interactions between the ligands and the PI3Kα protein.
Stable interactions between the DJ3 ligand atoms and active amino acid residues within the PI3Kα protein pocket during 100 ns MD simulation.
Stable interactions between the DJ7 ligand atoms and active amino acid residues within the PI3Kα protein pocket during 100 ns MD simulation.
Figure 8 highlights the crucial interactions responsible for the stability of the DJ3 ligand within the PI3Kα protein pocket, which include H-bonds, hydrophobic interactions, and water bridges. The H-bond interactions were observed between the DJ3 ligand and amino acid residues such as SER773 (80%), GLN859 (30%), and HIS855 (15%). Likewise, hydrophobic interactions were observed between DJ3 and amino acid residues, such as TRP780 (45%) and ILE932 (30%). In addition to these interactions, water bridges formed between DJ3 and amino acid residues such as GLN728, TYR836, HIS919, and GLN859, further contributing to the stability of DJ3 within the PI3Kα protein pocket.
Figure 9 reveals that H-bonds, hydrophobic interactions, water bridges, and weak ionic bonds contribute to the stability of the DJ7 ligand within the PI3Kα pocket. The H-bond interactions observed between DJ7 and amino acid residues such as SER773 (25%) and ASN920 (17%) played a crucial role in stabilizing the complex. Similarly, hydrophobic interactions between DJ7 and amino acid residues such as TRP780 (30%) and ILE932 (15%) were significant contributors to the stability of the complex. In addition, water bridges and weak ionic bonds between DJ7 and amino acid residues such as SER773 and ASP933 further stabilized the complex. The hydrophobic residues such as MET772, PRO778, and VAL850 also interacted with the DJ7 ligand, contributing to its stability within the PI3Kα pocket.
Figure 10 demonstrates that H-bonds, hydrophobic interactions, and water bridges are critical to the stability of the DJ18 ligand inside the active pocket of the PI3Kα protein. Specifically, the H-bond interaction between DJ18 and amino acid residue VAL851 significantly stabilizes the complex. In addition, hydrophobic interactions between DJ18 and amino acid residues such as ILE800 (37%), TYR836 (30%), and ILE932 (>40%) were crucial contributors to the stability of the complex. Moreover, water bridges were observed between DJ18 and amino acid residues such as TYR836 and GLN859, further stabilizing the complex. The hydrophobic residues MET772, PRO778, TRP780, ILE848, and MET922 also interacted with the DJ18 ligand, contributing to its stability inside the active pocket. Lastly, weak ionic bonds and water bridges were observed between DJ18 and amino acid residues such as VAL851, SER584, and ASP933, adding to the stability of the complex.
Stable interactions between the DJ18 ligand atoms and active amino acid residues within the PI3Kα protein pocket during 100 ns MD simulation.
A combination of H-bonds, hydrophobic forces, water bridges, and weak ionic bonds maintains the stability of Trastuzumab ligand within the PI3Kα pocket. Specifically, Trastuzumab interacts with amino acid residues such as SER773, SER774, and ASP933 through H-bonds, while hydrophobic interactions involve amino acid residues like TRP780, TYR836, and ILE800. Water and ion bridges also play a crucial role in interactions with ARG770 and GLN859, as shown in Figure 11.
Stable interactions between standard drug Trastuzumab ligand atoms and active amino acid residues within the PI3Kα protein pocket during 100 ns MD simulation.
3.5.3 Ligand properties
The variations in the properties of the ligands DJ3, DJ7, DJ18, and the reference drug Trastuzumab in the PI3Kα protein pocket during the MD simulation period from 0.00 to 100 ns are illustrated in a timeline format in Figure 12a–d.
Ligand RMSD
DURING THE MD SIMULATION, the RMSD values for the ligands DJ3, DJ7, DJ18, and Trastuzumab remained stable within specific ranges. Specifically, the RMSD values for DJ3 were between 0.5 and 1.2 Å, for DJ7 between 0.5 and 3 Å, for DJ18 between 0.5 and 1.5 Å, and for Trastuzumab between 0.3 and 1 Å.
Radius of gyration (rGyr)
Throughout the MD simulation period of 0–100 ns, the radius of gyration (rGyr) values remained stable for the ligands. The DJ3 ligand exhibited a stable rGyr between 4.05 and 4.50 Å, while DJ7 showed a stable rGyr in the 4–4.6 Å range. DJ18 ligand displayed a stable rGyr between 2.9 and3.2 Å, and Trastuzumab showed a stable rGyr between 4.5 and 4.9 Å.
Intra-molecular hydrogen bonds (IntraHB)
The 100 ns MD simulation observed that the DJ3 ligand exhibited 1–3 IntraHB contacts, while no such contacts were recorded for the DJ7 and Trastuzumab ligands.
Molecular surface area (MolSA)
Over the course of the 100 ns MD simulation, we observed remarkable stability in the molecular surface area (MolSA) levels for each ligand. The DJ3 ligand maintained a steady range between 376 and 392 Å2, while the DJ7 ligand ranged from 390 to 435 Å2. The DJ18 ligand showed stability between 208 and 216 Å2, and Trastuzumab displayed consistency in the range of 405 to 415 Å2. These findings suggest that these ligands maintain a stable conformation within the PI3Kα protein pocket during the simulation period.
Solvent-accessible surface area (SASA)
SASA of the ligands DJ3, DJ7, DJ18, and Trastuzumab were analyzed during the 100 ns duration of the MD simulation. It was observed that the SASA scores remained relatively stable for all the ligands. Specifically, the SASA score ranged from 120 to 200 Å2 for DJ3, 160 to 320 Å2 for DJ7, 50 to 100 Å2 for DJ18, and 180 to 300 Å2 for Trastuzumab. These findings suggest that the surface area of the ligands accessible to the solvent molecules remained almost constant during the simulation, indicating that the conformational changes of the ligands did not significantly affect their solvent accessibility.
Polar surface area
For the 100 ns MD simulation, we observed that the PSA values remained stable for each of the ligands. Specifically, the PSA was between 170 and 190 for DJ3, 160 to 200 Å2 for DJ7, 16–32 Å2 for DJ18, and 195–255 Å2 for Trastuzumab.
Properties of ligands DJ3, DJ7, DJ18, and Trastuzumab, including RMSD, the radius of gyration, intramolecular hydrogen bonding, molecular surface area, and solvent-accessible surface area: (a) PI3Kα–DJ03, (b) PI3Kα–DJ07, (c) PI3Kα–DJ18, and (d) PI3Kα–Tras.
3.6 MM-GBSA and MM-PBSA energy calculations
The results presented in Figure 13 showcase the binding energies of PI3Kα with various ligands, assessed through both MM-GBSA and MM-PBSA methods. Notably, DJ7 emerges as a ligand with the strongest binding affinity, demonstrating highly favorable energy components in both methods, particularly in van der Waals interactions and electrostatic energies. DJ3 also exhibits strong binding in MM-GBSA, but its performance in MM-PBSA is less optimal. DJ18, while displaying robust binding in MM-GBSA, shows relatively weaker binding in MM-PBSA. Trastuzumab demonstrates strong binding in MM-GBSA but moderate binding in MM-PBSA. These results offer valuable insights into the molecular interactions between these ligands and PI3Kα, suggesting DJ7 as a promising candidate for further investigation.
(a) MM-GBSA and (b) MM-PBSA binding energies of PI3Kα docked at active site of screened ligands. E bind = binding energy, E el = electrostatic energy, Sol_GB = solvation energy based on the generalized Born model, E vdw = van der waals interactions, E NPOLAR = polar solvation energy, E PB = polar solvation energy according to the Poisson–Boltzmann model, E DISPER = dispersion nonpolar solvation energy.
These MD results provide strong evidence for the stability and compatibility of the proposed drug ligands with the PI3Kα protein structure, suggesting their potential use for developing new breast cancer drugs targeting the PI3Kα pathway. Overall, the molecular and structural dynamics properties obtained through the MD simulations support the potential of these ligands for further drug discovery and design efforts.
The promising candidates DJ03, DJ07, and DJ18 derived from natural phloroglucinols show potential as breast cancer drug candidates targeting PI3Kα activity. To optimize their activities, structural modifications can be strategically implemented. Firstly, incorporating or substituting functional groups known to enhance binding affinity to PI3Kα, such as hydrophobic moieties, hydrogen bond acceptors, or electron-withdrawing groups, can improve their interactions with the target enzyme. Additionally, reducing steric hindrance by modifying bulky substituents and introducing conformational flexibility through rotatable bonds or flexible linkers can enhance their fit within the active site. Bio isosteric replacements and adjustments in hydrophobicity can further fine-tune their pharmacological properties, improving solubility, bioavailability, and membrane permeability. Rational design guided by computational modeling techniques, including molecular docking and MD simulations, can aid in predicting and optimizing these modifications. Moreover, evaluating and optimizing ADMET properties will ensure favorable pharmacokinetic profiles, enhancing the efficacy and safety of these modified molecules as potential breast cancer therapeutics. These strategies represent a promising approach towards developing innovative treatments for the deadliest forms of breast cancer, potentially revolutionizing current treatment strategies.
4 Conclusions
This study has unveiled the promising potential of bioactive compounds from Dryopteris species as a targeted therapy for breast cancer, particularly in inhibiting PI3Kα enzymatic activity. Moving forward, there are several avenues for expanding the scope of this research. First, the study could be extended to investigate other drug classes beyond phloroglucinols, exploring a broader range of natural compounds or synthetic derivatives that may exhibit superior efficacy or novel mechanisms of action against breast cancer targets. Additionally, considering the vast diversity of natural sources, such as medicinal plants, marine organisms, or microbial metabolites, future investigations could explore alternative natural products for their anticancer properties. However, it is essential to acknowledge the limitations of this study. One limitation is the focus on computational methods without experimental validation. Integrating in vitro and in vivo studies could provide robust validation of the computational findings and further elucidate the pharmacological mechanisms of the identified compounds. Moreover, the study primarily focused on PI3Kα activity; expanding the target repertoire to include other crucial signaling pathways or molecular targets implicated in breast cancer progression could provide a more comprehensive understanding of the therapeutic potential of the identified compounds. To address these limitations, a multi-disciplinary approach combining computational modeling, experimental validation, and pharmacological assays could be adopted. Collaborative efforts involving pharmacologists, chemists, and biologists can facilitate a holistic exploration of natural compounds for breast cancer therapy. Furthermore, employing advanced techniques such as high-throughput screening, metabolomics, and structural biology studies could accelerate the discovery and optimization of lead compounds from natural sources. In summary, while this study lays a solid foundation for the development of novel breast cancer drugs targeting PI3Kα activity, future endeavors should strive for a more comprehensive exploration of diverse drug classes, natural sources, and molecular targets, while integrating experimental validations and adopting a multi-disciplinary approach to address the study’s limitations and maximize its translational potential in clinical settings.
Acknowledgments
The authors appreciate the Researchers Supporting Project number (RSP2024R437), King Saud University, Riyadh, Saudi Arabia.
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Funding information: This work is financially supported by the Researchers Supporting Project number (RSP-2024R437), King Saud University, Riyadh, Saudi Arabia.
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Author contributions: Conceptualization, writing the original draft, reviewing and editing: Farhan Siddique, Monisa Ayoub, Souad Elkhattabi, and Samir Chtita; Formal analysis, investigations, funding acquisition, reviewing, and editing: Ossama Daoui, Samina Afzal, Abrar Mohyuddin, Iram Kaukab, and Syeda Abida Ejaz; Resources, data validation, data curation, and supervision: Farhan Siddique, Ossama Daouoi, Ahmad Mohammad Salamatullah, Samir Ibenmoussa, Gezahign Fentahun Wondmie, and Mohammed Bourhia.
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Conflict of interest: The authors reported that there is no conflict of interest.
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Ethical approval: The conducted research is not related to either human or animal use.
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Data availability statement: The raw/processed data required to reproduce these findings are shared as a zip file.
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- Response of yield and quality of Japonica rice to different gradients of moisture deficit at grain-filling stage in cold regions
- Preparation of an inclusion complex of nickel-based β-cyclodextrin: Characterization and accelerating the osteoarthritis articular cartilage repair
- Empagliflozin-loaded nanomicelles responsive to reactive oxygen species for renal ischemia/reperfusion injury protection
- Preparation and pharmacodynamic evaluation of sodium aescinate solid lipid nanoparticles
- Assessment of potentially toxic elements and health risks of agricultural soil in Southwest Riyadh, Saudi Arabia
- Theoretical investigation of hydrogen-rich fuel production through ammonia decomposition
- Biosynthesis and screening of cobalt nanoparticles using citrus species for antimicrobial activity
- Investigating the interplay of genetic variations, MCP-1 polymorphism, and docking with phytochemical inhibitors for combatting dengue virus pathogenicity through in silico analysis
- Ultrasound induced biosynthesis of silver nanoparticles embedded into chitosan polymers: Investigation of its anti-cutaneous squamous cell carcinoma effects
- Copper oxide nanoparticles-mediated Heliotropium bacciferum leaf extract: Antifungal activity and molecular docking assays against strawberry pathogens
- Sprouted wheat flour for improving physical, chemical, rheological, microbial load, and quality properties of fino bread
- Comparative toxicity assessment of fisetin-aided artificial intelligence-assisted drug design targeting epibulbar dermoid through phytochemicals
- Acute toxicity and anti-inflammatory activity of bis-thiourea derivatives
- Anti-diabetic activity-guided isolation of α-amylase and α-glucosidase inhibitory terpenes from Capsella bursa-pastoris Linn.
- GC–MS analysis of Lactobacillus plantarum YW11 metabolites and its computational analysis on familial pulmonary fibrosis hub genes
- Green formulation of copper nanoparticles by Pistacia khinjuk leaf aqueous extract: Introducing a novel chemotherapeutic drug for the treatment of prostate cancer
- Improved photocatalytic properties of WO3 nanoparticles for Malachite green dye degradation under visible light irradiation: An effect of La doping
- One-pot synthesis of a network of Mn2O3–MnO2–poly(m-methylaniline) composite nanorods on a polypyrrole film presents a promising and efficient optoelectronic and solar cell device
- Groundwater quality and health risk assessment of nitrate and fluoride in Al Qaseem area, Saudi Arabia
- A comparative study of the antifungal efficacy and phytochemical composition of date palm leaflet extracts
- Processing of alcohol pomelo beverage (Citrus grandis (L.) Osbeck) using saccharomyces yeast: Optimization, physicochemical quality, and sensory characteristics
- Specialized compounds of four Cameroonian spices: Isolation, characterization, and in silico evaluation as prospective SARS-CoV-2 inhibitors
- Identification of a novel drug target in Porphyromonas gingivalis by a computational genome analysis approach
- Physico-chemical properties and durability of a fly-ash-based geopolymer
- FMS-like tyrosine kinase 3 inhibitory potentials of some phytochemicals from anti-leukemic plants using computational chemical methodologies
- Wild Thymus zygis L. ssp. gracilis and Eucalyptus camaldulensis Dehnh.: Chemical composition, antioxidant and antibacterial activities of essential oils
- 3D-QSAR, molecular docking, ADMET, simulation dynamic, and retrosynthesis studies on new styrylquinolines derivatives against breast cancer
- Deciphering the influenza neuraminidase inhibitory potential of naturally occurring biflavonoids: An in silico approach
- Determination of heavy elements in agricultural regions, Saudi Arabia
- Synthesis and characterization of antioxidant-enriched Moringa oil-based edible oleogel
- Ameliorative effects of thistle and thyme honeys on cyclophosphamide-induced toxicity in mice
- Study of phytochemical compound and antipyretic activity of Chenopodium ambrosioides L. fractions
- Investigating the adsorption mechanism of zinc chloride-modified porous carbon for sulfadiazine removal from water
- Performance repair of building materials using alumina and silica composite nanomaterials with electrodynamic properties
- Effects of nanoparticles on the activity and resistance genes of anaerobic digestion enzymes in livestock and poultry manure containing the antibiotic tetracycline
- Effect of copper nanoparticles green-synthesized using Ocimum basilicum against Pseudomonas aeruginosa in mice lung infection model
- Cardioprotective effects of nanoparticles green formulated by Spinacia oleracea extract on isoproterenol-induced myocardial infarction in mice by the determination of PPAR-γ/NF-κB pathway
- Anti-OTC antibody-conjugated fluorescent magnetic/silica and fluorescent hybrid silica nanoparticles for oxytetracycline detection
- Curcumin conjugated zinc nanoparticles for the treatment of myocardial infarction
- Identification and in silico screening of natural phloroglucinols as potential PI3Kα inhibitors: A computational approach for drug discovery
- Exploring the phytochemical profile and antioxidant evaluation: Molecular docking and ADMET analysis of main compounds from three Solanum species in Saudi Arabia
- Unveiling the molecular composition and biological properties of essential oil derived from the leaves of wild Mentha aquatica L.: A comprehensive in vitro and in silico exploration
- Analysis of bioactive compounds present in Boerhavia elegans seeds by GC-MS
- Homology modeling and molecular docking study of corticotrophin-releasing hormone: An approach to treat stress-related diseases
- LncRNA MIR17HG alleviates heart failure via targeting MIR17HG/miR-153-3p/SIRT1 axis in in vitro model
- Development and validation of a stability indicating UPLC-DAD method coupled with MS-TQD for ramipril and thymoquinone in bioactive SNEDDS with in silico toxicity analysis of ramipril degradation products
- Biosynthesis of Ag/Cu nanocomposite mediated by Curcuma longa: Evaluation of its antibacterial properties against oral pathogens
- Development of AMBER-compliant transferable force field parameters for polytetrafluoroethylene
- Treatment of gestational diabetes by Acroptilon repens leaf aqueous extract green-formulated iron nanoparticles in rats
- Development and characterization of new ecological adsorbents based on cardoon wastes: Application to brilliant green adsorption
- A fast, sensitive, greener, and stability-indicating HPLC method for the standardization and quantitative determination of chlorhexidine acetate in commercial products
- Assessment of Se, As, Cd, Cr, Hg, and Pb content status in Ankang tea plantations of China
- Effect of transition metal chloride (ZnCl2) on low-temperature pyrolysis of high ash bituminous coal
- Evaluating polyphenol and ascorbic acid contents, tannin removal ability, and physical properties during hydrolysis and convective hot-air drying of cashew apple powder
- Development and characterization of functional low-fat frozen dairy dessert enhanced with dried lemongrass powder
- Scrutinizing the effect of additive and synergistic antibiotics against carbapenem-resistant Pseudomonas aeruginosa
- Preparation, characterization, and determination of the therapeutic effects of copper nanoparticles green-formulated by Pistacia atlantica in diabetes-induced cardiac dysfunction in rat
- Antioxidant and antidiabetic potentials of methoxy-substituted Schiff bases using in vitro, in vivo, and molecular simulation approaches
- Anti-melanoma cancer activity and chemical profile of the essential oil of Seseli yunnanense Franch
- Molecular docking analysis of subtilisin-like alkaline serine protease (SLASP) and laccase with natural biopolymers
- Overcoming methicillin resistance by methicillin-resistant Staphylococcus aureus: Computational evaluation of napthyridine and oxadiazoles compounds for potential dual inhibition of PBP-2a and FemA proteins
- Exploring novel antitubercular agents: Innovative design of 2,3-diaryl-quinoxalines targeting DprE1 for effective tuberculosis treatment
- Drimia maritima flowers as a source of biologically potent components: Optimization of bioactive compound extractions, isolation, UPLC–ESI–MS/MS, and pharmacological properties
- Estimating molecular properties, drug-likeness, cardiotoxic risk, liability profile, and molecular docking study to characterize binding process of key phyto-compounds against serotonin 5-HT2A receptor
- Fabrication of β-cyclodextrin-based microgels for enhancing solubility of Terbinafine: An in-vitro and in-vivo toxicological evaluation
- Phyto-mediated synthesis of ZnO nanoparticles and their sunlight-driven photocatalytic degradation of cationic and anionic dyes
- Monosodium glutamate induces hypothalamic–pituitary–adrenal axis hyperactivation, glucocorticoid receptors down-regulation, and systemic inflammatory response in young male rats: Impact on miR-155 and miR-218
- Quality control analyses of selected honey samples from Serbia based on their mineral and flavonoid profiles, and the invertase activity
- Eco-friendly synthesis of silver nanoparticles using Phyllanthus niruri leaf extract: Assessment of antimicrobial activity, effectiveness on tropical neglected mosquito vector control, and biocompatibility using a fibroblast cell line model
- Green synthesis of silver nanoparticles containing Cichorium intybus to treat the sepsis-induced DNA damage in the liver of Wistar albino rats
- Quality changes of durian pulp (Durio ziberhinus Murr.) in cold storage
- Study on recrystallization process of nitroguanidine by directly adding cold water to control temperature
- Determination of heavy metals and health risk assessment in drinking water in Bukayriyah City, Saudi Arabia
- Larvicidal properties of essential oils of three Artemisia species against the chemically insecticide-resistant Nile fever vector Culex pipiens (L.) (Diptera: Culicidae): In vitro and in silico studies
- Design, synthesis, characterization, and theoretical calculations, along with in silico and in vitro antimicrobial proprieties of new isoxazole-amide conjugates
- The impact of drying and extraction methods on total lipid, fatty acid profile, and cytotoxicity of Tenebrio molitor larvae
- A zinc oxide–tin oxide–nerolidol hybrid nanomaterial: Efficacy against esophageal squamous cell carcinoma
- Research on technological process for production of muskmelon juice (Cucumis melo L.)
- Physicochemical components, antioxidant activity, and predictive models for quality of soursop tea (Annona muricata L.) during heat pump drying
- Characterization and application of Fe1−xCoxFe2O4 nanoparticles in Direct Red 79 adsorption
- Torilis arvensis ethanolic extract: Phytochemical analysis, antifungal efficacy, and cytotoxicity properties
- Magnetite–poly-1H pyrrole dendritic nanocomposite seeded on poly-1H pyrrole: A promising photocathode for green hydrogen generation from sanitation water without using external sacrificing agent
- HPLC and GC–MS analyses of phytochemical compounds in Haloxylon salicornicum extract: Antibacterial and antifungal activity assessment of phytopathogens
- Efficient and stable to coking catalysts of ethanol steam reforming comprised of Ni + Ru loaded on MgAl2O4 + LnFe0.7Ni0.3O3 (Ln = La, Pr) nanocomposites prepared via cost-effective procedure with Pluronic P123 copolymer
- Nitrogen and boron co-doped carbon dots probe for selectively detecting Hg2+ in water samples and the detection mechanism
- Heavy metals in road dust from typical old industrial areas of Wuhan: Seasonal distribution and bioaccessibility-based health risk assessment
- Phytochemical profiling and bioactivity evaluation of CBD- and THC-enriched Cannabis sativa extracts: In vitro and in silico investigation of antioxidant and anti-inflammatory effects
- Investigating dye adsorption: The role of surface-modified montmorillonite nanoclay in kinetics, isotherms, and thermodynamics
- Antimicrobial activity, induction of ROS generation in HepG2 liver cancer cells, and chemical composition of Pterospermum heterophyllum
- Study on the performance of nanoparticle-modified PVDF membrane in delaying membrane aging
- Impact of cholesterol in encapsulated vitamin E acetate within cocoliposomes
- Review Articles
- Structural aspects of Pt(η3-X1N1X2)(PL) (X1,2 = O, C, or Se) and Pt(η3-N1N2X1)(PL) (X1 = C, S, or Se) derivatives
- Biosurfactants in biocorrosion and corrosion mitigation of metals: An overview
- Stimulus-responsive MOF–hydrogel composites: Classification, preparation, characterization, and their advancement in medical treatments
- Electrochemical dissolution of titanium under alternating current polarization to obtain its dioxide
- Special Issue on Recent Trends in Green Chemistry
- Phytochemical screening and antioxidant activity of Vitex agnus-castus L.
- Phytochemical study, antioxidant activity, and dermoprotective activity of Chenopodium ambrosioides (L.)
- Exploitation of mangliculous marine fungi, Amarenographium solium, for the green synthesis of silver nanoparticles and their activity against multiple drug-resistant bacteria
- Study of the phytotoxicity of margines on Pistia stratiotes L.
- Special Issue on Advanced Nanomaterials for Energy, Environmental and Biological Applications - Part III
- Impact of biogenic zinc oxide nanoparticles on growth, development, and antioxidant system of high protein content crop (Lablab purpureus L.) sweet
- Green synthesis, characterization, and application of iron and molybdenum nanoparticles and their composites for enhancing the growth of Solanum lycopersicum
- Green synthesis of silver nanoparticles from Olea europaea L. extracted polysaccharides, characterization, and its assessment as an antimicrobial agent against multiple pathogenic microbes
- Photocatalytic treatment of organic dyes using metal oxides and nanocomposites: A quantitative study
- Antifungal, antioxidant, and photocatalytic activities of greenly synthesized iron oxide nanoparticles
- Special Issue on Phytochemical and Pharmacological Scrutinization of Medicinal Plants
- Hepatoprotective effects of safranal on acetaminophen-induced hepatotoxicity in rats
- Chemical composition and biological properties of Thymus capitatus plants from Algerian high plains: A comparative and analytical study
- Chemical composition and bioactivities of the methanol root extracts of Saussurea costus
- In vivo protective effects of vitamin C against cyto-genotoxicity induced by Dysphania ambrosioides aqueous extract
- Insights about the deleterious impact of a carbamate pesticide on some metabolic immune and antioxidant functions and a focus on the protective ability of a Saharan shrub and its anti-edematous property
- A comprehensive review uncovering the anticancerous potential of genkwanin (plant-derived compound) in several human carcinomas
- A study to investigate the anticancer potential of carvacrol via targeting Notch signaling in breast cancer
- Assessment of anti-diabetic properties of Ziziphus oenopolia (L.) wild edible fruit extract: In vitro and in silico investigations through molecular docking analysis
- Optimization of polyphenol extraction, phenolic profile by LC-ESI-MS/MS, antioxidant, anti-enzymatic, and cytotoxic activities of Physalis acutifolia
- Phytochemical screening, antioxidant properties, and photo-protective activities of Salvia balansae de Noé ex Coss
- Antihyperglycemic, antiglycation, anti-hypercholesteremic, and toxicity evaluation with gas chromatography mass spectrometry profiling for Aloe armatissima leaves
- Phyto-fabrication and characterization of gold nanoparticles by using Timur (Zanthoxylum armatum DC) and their effect on wound healing
- Does Erodium trifolium (Cav.) Guitt exhibit medicinal properties? Response elements from phytochemical profiling, enzyme-inhibiting, and antioxidant and antimicrobial activities
- Integrative in silico evaluation of the antiviral potential of terpenoids and its metal complexes derived from Homalomena aromatica based on main protease of SARS-CoV-2
- 6-Methoxyflavone improves anxiety, depression, and memory by increasing monoamines in mice brain: HPLC analysis and in silico studies
- Simultaneous extraction and quantification of hydrophilic and lipophilic antioxidants in Solanum lycopersicum L. varieties marketed in Saudi Arabia
- Biological evaluation of CH3OH and C2H5OH of Berberis vulgaris for in vivo antileishmanial potential against Leishmania tropica in murine models
Articles in the same Issue
- Regular Articles
- Porous silicon nanostructures: Synthesis, characterization, and their antifungal activity
- Biochar from de-oiled Chlorella vulgaris and its adsorption on antibiotics
- Phytochemicals profiling, in vitro and in vivo antidiabetic activity, and in silico studies on Ajuga iva (L.) Schreb.: A comprehensive approach
- Synthesis, characterization, in silico and in vitro studies of novel glycoconjugates as potential antibacterial, antifungal, and antileishmanial agents
- Sonochemical synthesis of gold nanoparticles mediated by potato starch: Its performance in the treatment of esophageal cancer
- Computational study of ADME-Tox prediction of selected phytochemicals from Punica granatum peels
- Phytochemical analysis, in vitro antioxidant and antifungal activities of extracts and essential oil derived from Artemisia herba-alba Asso
- Two triazole-based coordination polymers: Synthesis and crystal structure characterization
- Phytochemical and physicochemical studies of different apple varieties grown in Morocco
- Synthesis of multi-template molecularly imprinted polymers (MT-MIPs) for isolating ethyl para-methoxycinnamate and ethyl cinnamate from Kaempferia galanga L., extract with methacrylic acid as functional monomer
- Nutraceutical potential of Mesembryanthemum forsskaolii Hochst. ex Bioss.: Insights into its nutritional composition, phytochemical contents, and antioxidant activity
- Evaluation of influence of Butea monosperma floral extract on inflammatory biomarkers
- Cannabis sativa L. essential oil: Chemical composition, anti-oxidant, anti-microbial properties, and acute toxicity: In vitro, in vivo, and in silico study
- The effect of gamma radiation on 5-hydroxymethylfurfural conversion in water and dimethyl sulfoxide
- Hollow mushroom nanomaterials for potentiometric sensing of Pb2+ ions in water via the intercalation of iodide ions into the polypyrrole matrix
- Determination of essential oil and chemical composition of St. John’s Wort
- Computational design and in vitro assay of lantadene-based novel inhibitors of NS3 protease of dengue virus
- Anti-parasitic activity and computational studies on a novel labdane diterpene from the roots of Vachellia nilotica
- Microbial dynamics and dehydrogenase activity in tomato (Lycopersicon esculentum Mill.) rhizospheres: Impacts on growth and soil health across different soil types
- Correlation between in vitro anti-urease activity and in silico molecular modeling approach of novel imidazopyridine–oxadiazole hybrids derivatives
- Spatial mapping of indoor air quality in a light metro system using the geographic information system method
- Iron indices and hemogram in renal anemia and the improvement with Tribulus terrestris green-formulated silver nanoparticles applied on rat model
- Integrated track of nano-informatics coupling with the enrichment concept in developing a novel nanoparticle targeting ERK protein in Naegleria fowleri
- Cytotoxic and phytochemical screening of Solanum lycopersicum–Daucus carota hydro-ethanolic extract and in silico evaluation of its lycopene content as anticancer agent
- Protective activities of silver nanoparticles containing Panax japonicus on apoptotic, inflammatory, and oxidative alterations in isoproterenol-induced cardiotoxicity
- pH-based colorimetric detection of monofunctional aldehydes in liquid and gas phases
- Investigating the effect of resveratrol on apoptosis and regulation of gene expression of Caco-2 cells: Unravelling potential implications for colorectal cancer treatment
- Metformin inhibits knee osteoarthritis induced by type 2 diabetes mellitus in rats: S100A8/9 and S100A12 as players and therapeutic targets
- Effect of silver nanoparticles formulated by Silybum marianum on menopausal urinary incontinence in ovariectomized rats
- Synthesis of new analogs of N-substituted(benzoylamino)-1,2,3,6-tetrahydropyridines
- Response of yield and quality of Japonica rice to different gradients of moisture deficit at grain-filling stage in cold regions
- Preparation of an inclusion complex of nickel-based β-cyclodextrin: Characterization and accelerating the osteoarthritis articular cartilage repair
- Empagliflozin-loaded nanomicelles responsive to reactive oxygen species for renal ischemia/reperfusion injury protection
- Preparation and pharmacodynamic evaluation of sodium aescinate solid lipid nanoparticles
- Assessment of potentially toxic elements and health risks of agricultural soil in Southwest Riyadh, Saudi Arabia
- Theoretical investigation of hydrogen-rich fuel production through ammonia decomposition
- Biosynthesis and screening of cobalt nanoparticles using citrus species for antimicrobial activity
- Investigating the interplay of genetic variations, MCP-1 polymorphism, and docking with phytochemical inhibitors for combatting dengue virus pathogenicity through in silico analysis
- Ultrasound induced biosynthesis of silver nanoparticles embedded into chitosan polymers: Investigation of its anti-cutaneous squamous cell carcinoma effects
- Copper oxide nanoparticles-mediated Heliotropium bacciferum leaf extract: Antifungal activity and molecular docking assays against strawberry pathogens
- Sprouted wheat flour for improving physical, chemical, rheological, microbial load, and quality properties of fino bread
- Comparative toxicity assessment of fisetin-aided artificial intelligence-assisted drug design targeting epibulbar dermoid through phytochemicals
- Acute toxicity and anti-inflammatory activity of bis-thiourea derivatives
- Anti-diabetic activity-guided isolation of α-amylase and α-glucosidase inhibitory terpenes from Capsella bursa-pastoris Linn.
- GC–MS analysis of Lactobacillus plantarum YW11 metabolites and its computational analysis on familial pulmonary fibrosis hub genes
- Green formulation of copper nanoparticles by Pistacia khinjuk leaf aqueous extract: Introducing a novel chemotherapeutic drug for the treatment of prostate cancer
- Improved photocatalytic properties of WO3 nanoparticles for Malachite green dye degradation under visible light irradiation: An effect of La doping
- One-pot synthesis of a network of Mn2O3–MnO2–poly(m-methylaniline) composite nanorods on a polypyrrole film presents a promising and efficient optoelectronic and solar cell device
- Groundwater quality and health risk assessment of nitrate and fluoride in Al Qaseem area, Saudi Arabia
- A comparative study of the antifungal efficacy and phytochemical composition of date palm leaflet extracts
- Processing of alcohol pomelo beverage (Citrus grandis (L.) Osbeck) using saccharomyces yeast: Optimization, physicochemical quality, and sensory characteristics
- Specialized compounds of four Cameroonian spices: Isolation, characterization, and in silico evaluation as prospective SARS-CoV-2 inhibitors
- Identification of a novel drug target in Porphyromonas gingivalis by a computational genome analysis approach
- Physico-chemical properties and durability of a fly-ash-based geopolymer
- FMS-like tyrosine kinase 3 inhibitory potentials of some phytochemicals from anti-leukemic plants using computational chemical methodologies
- Wild Thymus zygis L. ssp. gracilis and Eucalyptus camaldulensis Dehnh.: Chemical composition, antioxidant and antibacterial activities of essential oils
- 3D-QSAR, molecular docking, ADMET, simulation dynamic, and retrosynthesis studies on new styrylquinolines derivatives against breast cancer
- Deciphering the influenza neuraminidase inhibitory potential of naturally occurring biflavonoids: An in silico approach
- Determination of heavy elements in agricultural regions, Saudi Arabia
- Synthesis and characterization of antioxidant-enriched Moringa oil-based edible oleogel
- Ameliorative effects of thistle and thyme honeys on cyclophosphamide-induced toxicity in mice
- Study of phytochemical compound and antipyretic activity of Chenopodium ambrosioides L. fractions
- Investigating the adsorption mechanism of zinc chloride-modified porous carbon for sulfadiazine removal from water
- Performance repair of building materials using alumina and silica composite nanomaterials with electrodynamic properties
- Effects of nanoparticles on the activity and resistance genes of anaerobic digestion enzymes in livestock and poultry manure containing the antibiotic tetracycline
- Effect of copper nanoparticles green-synthesized using Ocimum basilicum against Pseudomonas aeruginosa in mice lung infection model
- Cardioprotective effects of nanoparticles green formulated by Spinacia oleracea extract on isoproterenol-induced myocardial infarction in mice by the determination of PPAR-γ/NF-κB pathway
- Anti-OTC antibody-conjugated fluorescent magnetic/silica and fluorescent hybrid silica nanoparticles for oxytetracycline detection
- Curcumin conjugated zinc nanoparticles for the treatment of myocardial infarction
- Identification and in silico screening of natural phloroglucinols as potential PI3Kα inhibitors: A computational approach for drug discovery
- Exploring the phytochemical profile and antioxidant evaluation: Molecular docking and ADMET analysis of main compounds from three Solanum species in Saudi Arabia
- Unveiling the molecular composition and biological properties of essential oil derived from the leaves of wild Mentha aquatica L.: A comprehensive in vitro and in silico exploration
- Analysis of bioactive compounds present in Boerhavia elegans seeds by GC-MS
- Homology modeling and molecular docking study of corticotrophin-releasing hormone: An approach to treat stress-related diseases
- LncRNA MIR17HG alleviates heart failure via targeting MIR17HG/miR-153-3p/SIRT1 axis in in vitro model
- Development and validation of a stability indicating UPLC-DAD method coupled with MS-TQD for ramipril and thymoquinone in bioactive SNEDDS with in silico toxicity analysis of ramipril degradation products
- Biosynthesis of Ag/Cu nanocomposite mediated by Curcuma longa: Evaluation of its antibacterial properties against oral pathogens
- Development of AMBER-compliant transferable force field parameters for polytetrafluoroethylene
- Treatment of gestational diabetes by Acroptilon repens leaf aqueous extract green-formulated iron nanoparticles in rats
- Development and characterization of new ecological adsorbents based on cardoon wastes: Application to brilliant green adsorption
- A fast, sensitive, greener, and stability-indicating HPLC method for the standardization and quantitative determination of chlorhexidine acetate in commercial products
- Assessment of Se, As, Cd, Cr, Hg, and Pb content status in Ankang tea plantations of China
- Effect of transition metal chloride (ZnCl2) on low-temperature pyrolysis of high ash bituminous coal
- Evaluating polyphenol and ascorbic acid contents, tannin removal ability, and physical properties during hydrolysis and convective hot-air drying of cashew apple powder
- Development and characterization of functional low-fat frozen dairy dessert enhanced with dried lemongrass powder
- Scrutinizing the effect of additive and synergistic antibiotics against carbapenem-resistant Pseudomonas aeruginosa
- Preparation, characterization, and determination of the therapeutic effects of copper nanoparticles green-formulated by Pistacia atlantica in diabetes-induced cardiac dysfunction in rat
- Antioxidant and antidiabetic potentials of methoxy-substituted Schiff bases using in vitro, in vivo, and molecular simulation approaches
- Anti-melanoma cancer activity and chemical profile of the essential oil of Seseli yunnanense Franch
- Molecular docking analysis of subtilisin-like alkaline serine protease (SLASP) and laccase with natural biopolymers
- Overcoming methicillin resistance by methicillin-resistant Staphylococcus aureus: Computational evaluation of napthyridine and oxadiazoles compounds for potential dual inhibition of PBP-2a and FemA proteins
- Exploring novel antitubercular agents: Innovative design of 2,3-diaryl-quinoxalines targeting DprE1 for effective tuberculosis treatment
- Drimia maritima flowers as a source of biologically potent components: Optimization of bioactive compound extractions, isolation, UPLC–ESI–MS/MS, and pharmacological properties
- Estimating molecular properties, drug-likeness, cardiotoxic risk, liability profile, and molecular docking study to characterize binding process of key phyto-compounds against serotonin 5-HT2A receptor
- Fabrication of β-cyclodextrin-based microgels for enhancing solubility of Terbinafine: An in-vitro and in-vivo toxicological evaluation
- Phyto-mediated synthesis of ZnO nanoparticles and their sunlight-driven photocatalytic degradation of cationic and anionic dyes
- Monosodium glutamate induces hypothalamic–pituitary–adrenal axis hyperactivation, glucocorticoid receptors down-regulation, and systemic inflammatory response in young male rats: Impact on miR-155 and miR-218
- Quality control analyses of selected honey samples from Serbia based on their mineral and flavonoid profiles, and the invertase activity
- Eco-friendly synthesis of silver nanoparticles using Phyllanthus niruri leaf extract: Assessment of antimicrobial activity, effectiveness on tropical neglected mosquito vector control, and biocompatibility using a fibroblast cell line model
- Green synthesis of silver nanoparticles containing Cichorium intybus to treat the sepsis-induced DNA damage in the liver of Wistar albino rats
- Quality changes of durian pulp (Durio ziberhinus Murr.) in cold storage
- Study on recrystallization process of nitroguanidine by directly adding cold water to control temperature
- Determination of heavy metals and health risk assessment in drinking water in Bukayriyah City, Saudi Arabia
- Larvicidal properties of essential oils of three Artemisia species against the chemically insecticide-resistant Nile fever vector Culex pipiens (L.) (Diptera: Culicidae): In vitro and in silico studies
- Design, synthesis, characterization, and theoretical calculations, along with in silico and in vitro antimicrobial proprieties of new isoxazole-amide conjugates
- The impact of drying and extraction methods on total lipid, fatty acid profile, and cytotoxicity of Tenebrio molitor larvae
- A zinc oxide–tin oxide–nerolidol hybrid nanomaterial: Efficacy against esophageal squamous cell carcinoma
- Research on technological process for production of muskmelon juice (Cucumis melo L.)
- Physicochemical components, antioxidant activity, and predictive models for quality of soursop tea (Annona muricata L.) during heat pump drying
- Characterization and application of Fe1−xCoxFe2O4 nanoparticles in Direct Red 79 adsorption
- Torilis arvensis ethanolic extract: Phytochemical analysis, antifungal efficacy, and cytotoxicity properties
- Magnetite–poly-1H pyrrole dendritic nanocomposite seeded on poly-1H pyrrole: A promising photocathode for green hydrogen generation from sanitation water without using external sacrificing agent
- HPLC and GC–MS analyses of phytochemical compounds in Haloxylon salicornicum extract: Antibacterial and antifungal activity assessment of phytopathogens
- Efficient and stable to coking catalysts of ethanol steam reforming comprised of Ni + Ru loaded on MgAl2O4 + LnFe0.7Ni0.3O3 (Ln = La, Pr) nanocomposites prepared via cost-effective procedure with Pluronic P123 copolymer
- Nitrogen and boron co-doped carbon dots probe for selectively detecting Hg2+ in water samples and the detection mechanism
- Heavy metals in road dust from typical old industrial areas of Wuhan: Seasonal distribution and bioaccessibility-based health risk assessment
- Phytochemical profiling and bioactivity evaluation of CBD- and THC-enriched Cannabis sativa extracts: In vitro and in silico investigation of antioxidant and anti-inflammatory effects
- Investigating dye adsorption: The role of surface-modified montmorillonite nanoclay in kinetics, isotherms, and thermodynamics
- Antimicrobial activity, induction of ROS generation in HepG2 liver cancer cells, and chemical composition of Pterospermum heterophyllum
- Study on the performance of nanoparticle-modified PVDF membrane in delaying membrane aging
- Impact of cholesterol in encapsulated vitamin E acetate within cocoliposomes
- Review Articles
- Structural aspects of Pt(η3-X1N1X2)(PL) (X1,2 = O, C, or Se) and Pt(η3-N1N2X1)(PL) (X1 = C, S, or Se) derivatives
- Biosurfactants in biocorrosion and corrosion mitigation of metals: An overview
- Stimulus-responsive MOF–hydrogel composites: Classification, preparation, characterization, and their advancement in medical treatments
- Electrochemical dissolution of titanium under alternating current polarization to obtain its dioxide
- Special Issue on Recent Trends in Green Chemistry
- Phytochemical screening and antioxidant activity of Vitex agnus-castus L.
- Phytochemical study, antioxidant activity, and dermoprotective activity of Chenopodium ambrosioides (L.)
- Exploitation of mangliculous marine fungi, Amarenographium solium, for the green synthesis of silver nanoparticles and their activity against multiple drug-resistant bacteria
- Study of the phytotoxicity of margines on Pistia stratiotes L.
- Special Issue on Advanced Nanomaterials for Energy, Environmental and Biological Applications - Part III
- Impact of biogenic zinc oxide nanoparticles on growth, development, and antioxidant system of high protein content crop (Lablab purpureus L.) sweet
- Green synthesis, characterization, and application of iron and molybdenum nanoparticles and their composites for enhancing the growth of Solanum lycopersicum
- Green synthesis of silver nanoparticles from Olea europaea L. extracted polysaccharides, characterization, and its assessment as an antimicrobial agent against multiple pathogenic microbes
- Photocatalytic treatment of organic dyes using metal oxides and nanocomposites: A quantitative study
- Antifungal, antioxidant, and photocatalytic activities of greenly synthesized iron oxide nanoparticles
- Special Issue on Phytochemical and Pharmacological Scrutinization of Medicinal Plants
- Hepatoprotective effects of safranal on acetaminophen-induced hepatotoxicity in rats
- Chemical composition and biological properties of Thymus capitatus plants from Algerian high plains: A comparative and analytical study
- Chemical composition and bioactivities of the methanol root extracts of Saussurea costus
- In vivo protective effects of vitamin C against cyto-genotoxicity induced by Dysphania ambrosioides aqueous extract
- Insights about the deleterious impact of a carbamate pesticide on some metabolic immune and antioxidant functions and a focus on the protective ability of a Saharan shrub and its anti-edematous property
- A comprehensive review uncovering the anticancerous potential of genkwanin (plant-derived compound) in several human carcinomas
- A study to investigate the anticancer potential of carvacrol via targeting Notch signaling in breast cancer
- Assessment of anti-diabetic properties of Ziziphus oenopolia (L.) wild edible fruit extract: In vitro and in silico investigations through molecular docking analysis
- Optimization of polyphenol extraction, phenolic profile by LC-ESI-MS/MS, antioxidant, anti-enzymatic, and cytotoxic activities of Physalis acutifolia
- Phytochemical screening, antioxidant properties, and photo-protective activities of Salvia balansae de Noé ex Coss
- Antihyperglycemic, antiglycation, anti-hypercholesteremic, and toxicity evaluation with gas chromatography mass spectrometry profiling for Aloe armatissima leaves
- Phyto-fabrication and characterization of gold nanoparticles by using Timur (Zanthoxylum armatum DC) and their effect on wound healing
- Does Erodium trifolium (Cav.) Guitt exhibit medicinal properties? Response elements from phytochemical profiling, enzyme-inhibiting, and antioxidant and antimicrobial activities
- Integrative in silico evaluation of the antiviral potential of terpenoids and its metal complexes derived from Homalomena aromatica based on main protease of SARS-CoV-2
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- Simultaneous extraction and quantification of hydrophilic and lipophilic antioxidants in Solanum lycopersicum L. varieties marketed in Saudi Arabia
- Biological evaluation of CH3OH and C2H5OH of Berberis vulgaris for in vivo antileishmanial potential against Leishmania tropica in murine models
