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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

  • Mohammed Bourhia EMAIL logo , Muhammad Shahab , Guojun Zheng , Mohamed Taibi , Amine Elbouzidi , Ahmad Mohammad Salamatullah , Musaab Dauelbait EMAIL logo and Abdeslam Asehraou
Published/Copyright: October 2, 2024
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Open Chemistry
From the journal Open Chemistry Volume 22 Issue 1

Abstract

The treatment of the various infections caused by Staphylococcus aureus has become challenging due to the evolving resistance against current therapeutics. In this study, the potentials of napthyridine and oxadiazole derivatives to serve as dual inhibitors of penicillin-binding protein 2a (PBP-2a) and FemA protein, which are crucial to resistance to methicillin-based drugs by S. aureus, were evaluated using molecular modeling techniques. Seventy-two compounds were subjected to molecular docking against the proteins, and the hit compounds were subjected to drug-likeness evaluation and in silico pharmacokinetics prediction. The compounds with good safety profiles were subjected to a 250-ns molecular dynamics (MD) simulation and other relevant analyses based on the MD trajectories. Five hit compounds were selected based on their high affinity for the targets as evidenced by their docking scores ranging from −8.6 to −10.1 kcal/mol for PBP-2a and −9.6 to −9.9 kcal/mol for FemA. These compounds also passed Lipinski’s rule of five evaluation with no violation and possessed high human intestinal absorption potential, showcasing their potential as orally administered therapeutic agents. However, three of the compounds were potential mutagens. MD simulation revealed that the final two compounds maintained stable interactions with the target proteins over 250 ns, with minimal deviations and fluctuations. Hydrogen bond stability and energy decomposition analysis further confirmed the strong binding affinity of the hit compounds compared to the control drug, methicillin. Conclusively, the compounds with the CID “135964525” and “44130718” are worthy of further experimental validation in the development of potential inhibitors of PBP-2a and FemA.

Keywords: methicillin-resistance; Staphylococcus aureus ; napthyridine compound; oxadiazoles compound; PBP-2a protein; FemA protein

1 Introduction

Staphylococcus aureus, commonly known as S. aureus, is a versatile and medically significant bacterial species that continues to be a formidable public health threat worldwide [1]. First identified in the late 19th century by Sir Alexander Ogston, S. aureus quickly gained notoriety as a leading causative agent of various infectious diseases [2]. Its ability to colonize and infect a wide range of host tissues and evade the human immune response has rendered it a cynosure in scientific research. Initially, S. aureus was primarily associated with skin and soft tissue infections; however, it has now expanded its repertoire to include more invasive and life-threatening diseases, such as bacteremia, endocarditis, osteomyelitis, and necrotizing pneumonia [3]. S. aureus is a highly contagious bacterium that can spread via direct or indirect contact with infected people or contaminated surfaces. The most common mode of transmission is through skin-to-skin contact, particularly in crowded settings such as hospitals, schools, and athletic facilities [4]. S. aureus can also be transmitted through contact with infected wounds, sores, or lesions on the skin, a mode of transmission that is mostly prevalent in healthcare settings, where patients with open wounds or surgical incisions are at elevated risk of infection [5].

The treatment of infections caused by S. aureus presents significant challenges, particularly because of the rise of antibiotic-resistant strains like methicillin-resistant Staphylococcus aureus (MRSA) [6]. A notable strategy employed in the treatment of S. aureus infection involves a combination of antimicrobial therapies due to the reduced efficacy of monotherapies [7]. In resistant strains such as MRSA, certain cellular proteins are responsible for the development of resistance to antimicrobials, exemplifying this is the penicillin-binding protein 2a (PBP-2a). PBP-2a is a crucial enzyme in MRSA, responsible for cell wall biosynthesis, and it plays a key role in MRSA’s resistance to β-lactam antibiotics [8]. Generally, β-lactam antibiotics mediate deleterious actions on S. aureus by inhibiting the production of peptidoglycan in reactions catalyzed by penicillin-binding proteins (PBPs) [9]. The peptidoglycan is an essential component of the bacterial cell wall, and its inhibition leads to cell lysis and bacterial death. However, MRSA, through the action of PBP-2a, has developed a mechanism to resist the effects of β-lactam antibiotics [8]. The PBP-2a proceeds to mediate the transpeptidase reaction required for peptidoglycan biosynthesis, even in the presence of β-lactam drugs [10], contributing significantly to MRSA’s ability to endure and multiply even when β-lactam antibiotics are present, ultimately rendering the traditional treatment ineffective. Similarly, the FemA protein, encoded by the Fem genes, is a cytoplasmic protein which is crucial for the expression of methicillin resistance in MRSA. It has been reported to mediate the expression of the mecA gene, which encodes the PBP-2a protein, intriguingly, the absence of FemA conferred susceptibility to methicillin [11,12]. As a result, inhibiting these proteins has become a promising strategy for fighting S. aureus infections.

Napthyridine and oxadiazoles derivatives have garnered attention in medicinal chemistry research for their potential to combat microbial infections and other diseases. Specifically, napthyridine derivatives have shown pharmacological effects, such as antiviral, anticancer, anti-inflammatory, antimalarial, and antiprotozoal, among various other properties [13,14,15]. Similarly, oxidiazole derivatives have shown a broad spectrum of pharmacological properties, including antioxidant, anthelmintic, anti-inflammatory, cytotoxic, and anticonvulsant activities [16], with some reported to also possess antitubercular, anti-HIV, anti-hypertensive, and anticancer properties [17]. Consequently, both napthyridine and oxadiazole derivatives are explored in drug discovery studies against a wide range of infections.

This study aims to evaluate the potentials of the derivatives of napthyridine and oxadiazoles derivatives as inhibitors of the PBP-2a of S. aureus using computer-aided drug design (CADD) including virtual screening, drug-likeness evaluation, and pharmacokinetics properties profiling, quantum mechanical calculations, and molecular dynamics (MD) simulation. It is worth noting that CADD has shifted the paradigm in drug discovery by improving the cost- and time-effectiveness of this process [18].

2 Methods

2.1 Ligand retrieval and preparation

Oxadiazoles and napthyridine derivatives were identified by searching the PubChem database (https://pubchem.ncbi.nlm.nih.gov/). The keywords “napthyridine” and “oxadiazoles” were used to identify the respective napthyridine and oxadiazole derivatives available on the PubChem database. The identified derivative structures were obtained in structure data format [19,20] and were imported into PyRx via the incorporated OpenBabel module. Subsequently, the structures were subjected to energy minimization using the universal forcefield and the conjugate gradients algorithm [21].

2.2 Target structure retrieval and preparation

The three-dimensional (3D) structure of PBP-2a was elucidated using the X-ray diffraction method obtained from the Protein Databank (PDB) (https://www.rcsb.org/) [22] in PDB format using the PDB ID: 5M18 [23]. Also, the 3D structure of FemA was retrieved with the PDB ID: 1LRZ [24]. Sequel to the retrieval of the structure, it was prepared using the Dock prep module of UCSF Chimera v1.10.2 software program [25]. The preparation steps involved removing heteroatoms, water molecules, and associated ligands while restoring missing hydrogen atoms and charge ions. Subsequently, the Dock-prepped structure was subjected to energy minimization procedures using the energy minimization algorithm of the Swiss-PdbViewer v.4.10 software program [19,26]. Noteworthy, the energy minimization of the protein structure was done in vacuo using the GROMOS 43B1 forcefield which allows the evaluation of the energy of a structure as well as the repairing of distorted geometries [26].

2.3 Molecular docking simulation

A flexible docking protocol was employed to study the interaction of the compounds with the PBP-2a using the VINA module incorporated into the Python Prescription suite v.0.8 [27]. For the PBP-2a, the amino acid residues that constitute the active site of the protein were firstly delineated using the BIOVIA Discovery studio visualizer, after which a grid box of size x = 17.1656237844 Å, y = 22.4011654882 Å, and z = 12.9173766199 Å, with a center dimension of x = 17.4802893733, y = −18.9999491012, and z = −50.2219055 were set to define the active site. Conversely, a blind docking protocol was employed to study the interactions of the compounds with FemA, the grid box with size x = 68.8990970136 Å, y = 85.8606218435 Å, and z = 52.064913585 Å, with a center dimension of x = 35.0115192852, y = 68.8214808942, and z = 94.3147800551 was found to cover every residue of the protein. The docking procedure was initially executed using the default exhaustiveness of “8,” and finally, using the highest exhaustiveness of “32” which is available for AutoDock Vina. Following the docking simulation, the interactions of the protein with the ligands were studied using BIOVIA Discovery Studio [28].

2.4 Druglikeness and pharmacokinetics properties profiling

The Simplified Molecular Input Line Entry System (SMILES) of the hit compounds identified after the docking simulation were retrieved from the PubChem database and utilized for evaluating the drug-likeness of the compounds in accordance with Lipinski’s rule of five (Ro5) [29]. The SwissADME webserver (https://www.swissadme.ch.index.php/) was employed for this purpose [30], while the pharmacokinetics and toxicity profiles of the compounds were assessed using the pkCSM server (https://biosig.lab.uq.edu.au/pkcsm/prediction) [31].

2.5 MD simulation of top-scoring hits

The top-scoring viable hits for each of the protein and control drugs were subjected to MD simulation and free energy calculation-based validation was performed using AMBER v.22 (Case et al. [32]; Pearlman et al. [33]). The TIP3P water model was used, and the system was neutralized by Na+ counter ions addition (Wang et al. [34]). The General Amber Force Field-2 (GAFF2) was used to parameterize the small selected molecules [35] with the estimation of AM1-BCC charges [35]. The steepest descent algorithm was used to minimize the energy of the system. Prior to the simulations, a restricting simulation of position for equilibration around both system and solvent with protein was carried out. MD simulation studies of the system were performed using NPT and NVT ensembles with a fixed number of atoms, volume, pressure, and temperature. Hydrogen bonds were constrained by the Particle Mesh Ewald SHAKE algorithm. Finally, 200 ns MD simulation was performed for each system. The MD trajectories were analyzed by root mean square deviation (RMSD), root mean square fluctuation (RMSF), etc., using CPPTRAJ and PYTRAJ. Visualization was performed with PyMol [36]. Furthermore, we also calculated the total energies of all the systems, including control and final hits.

2.5.1 Binding free energy calculations

We computed the binding free energy of WT-MT complexes using the MMGBSA method [37]. The calculation was performed on 20,000 conformations collected after each 0.2 ns in the course of all-atom (200 ns) trajectories. Two widely used methods to calculate the free energy are mechanics Poisson–Boltzmann surface area (MM/PBSA) and molecular mechanics/generalized Born surface area (MM/GBSA). Experimental approaches are corroborated by the values of MM/PBSA [38]. In protein–protein interaction and protein-ligand binding, MM/PBSA has been widely used. In our case, we run each using the MMPBSA and MMGBSA approach to calculate the binding free energy.

The following equation was used for free energy calculation:

∆ G ( bind ) = ∆ G ( complex ) − [ ∆ G ( receptor ) + ∆ G ( ligand ) ] ,

G = G bond + G ele + G vdW + G pol + G npol − TS .

Here, G bond, G ele, and G vdW refer to bonded, electrostatic, and van der Waals (vdW) interactions, respectively. G pol and G npol are polar and nonpolar solvated free energies. The G pol and G npol are calculated by the generalized Born (GB) implicit solvent method with the solvent-accessible surface area (SASA) term. We additionally carried out per-residues energy decomposition analysis to identify which residue contributes how much of the total interaction (energy).

3 Results and discussion

3.1 Retrieved ligands and target structures

A thorough search of the PubChem database revealed 12 oxadiazoles and 65 naphthyridine derivatives of which the oxadiazoles were majorly the 1,3,4-oxadiazole while the naphthyridine derivatives included the 1,5-napthyridine, 1,6-napthyridine, 1,7-napthyridine, and 1,8-napthyridine derivatives. The structure of PBP-2a with a resolution of 1.98 Å was retrieved in a complex with cefepime ligand, structural analysis revealed the protein to be a homodimer composed of 642 amino acid residues. Conversely, the retrieved FemA structure has a resolution of 2.1 Å, was not in complex with an inhibitor, and is composed of 426 amino acid residues. The retrieved structures of the protein are depicted in Figure S1. In preparation for molecular docking, the chain A of the PBP-2a was selected and prepared, while structures of FemA and the ligands were also prepared.

3.2 Molecular docking simulation

The docking simulation results revealed the exhaustiveness parameter greatly affects the docking scores of the compounds for the proteins, with the “32” exhaustiveness value correlating to lower docking scores on most occasions. As presented in the Supplementary material, the compounds with the CIDs “9965471,” “89995619,” “85199,” and “66997784” had initial docking scores of −6.8, −5.9, −6.0, and −9.2 kcal/mol, respectively, against FemA when the exhaustiveness parameter value was “8,” interestingly, the docking scores further increased to −6.6, −5.3, −5.7, and −7.9 kcal/mol, respectively, when the exhaustiveness parameter was set to “32,” indicating the elimination of false positives. Similarly, the compounds with the CIDs “10129935,” “10523409,” “10546084,” and “10571743” had initial docking scores of −3.9, −8.5, −7.7, and −8.4 kcal/mol, respectively, against PBP-2a, while the final docking scores were −3.9, −8.0, −7.5, and −8.4 kcal/mol. Consequently, the hit compounds of this study were selected based on the docking scores obtained with the exhaustiveness set to “32,” and the selected compounds are presented in Table 1. As evident in the table, the selected compounds possessed higher affinities for the proteins compared to methicillin.

Table 1

The docking scores of the hit compounds against PBP-2a and FemA proteins

S/N Compound CID Docking scores (kcal/mol)
PBP-2a FemA
1 135964525 −10.1 −9.8
2 44130718 −9.5 −9.9
3 135438537 −9.1 −9.4
4 135505656 −9.1 −9.4
5 135520508 −8.6 −9.6
6 Methicillin −6.4 −6.6

3.3 Molecular interaction profiling

The interactions of the hit compounds of this study with PBP-2a and FemA are depicted in Figures 1 and 2, respectively. The compounds interacted with multiple amino acid residues in the binding site of the proteins, with many interactions including vdW interactions, hydrogen bonds, pi-sigma, and pi-sulfur bonds present.

Figure 1 The interaction of the hit compounds of this study with PBP-2a protein. (a) PBP2a-44130718; (b) PBP2a-44130718; (c) PBP2a-135505656; (d) PBP2a-135520508; (e) PBP2a-135964525; and (f) PBP2a-Methicillin.
Figure 1

The interaction of the hit compounds of this study with PBP-2a protein. (a) PBP2a-44130718; (b) PBP2a-44130718; (c) PBP2a-135505656; (d) PBP2a-135520508; (e) PBP2a-135964525; and (f) PBP2a-Methicillin.

Figure 2 The interaction of the hit compounds of this study with FemA protein. (a) FemA-44130718; (b) FemA-44130718; (c) FemA-135505656; (d) FemA-135520508; (e) FemA-135964525; and (f) FemA-methicillin.
Figure 2

The interaction of the hit compounds of this study with FemA protein. (a) FemA-44130718; (b) FemA-44130718; (c) FemA-135505656; (d) FemA-135520508; (e) FemA-135964525; and (f) FemA-methicillin.

3.4 Drug-likeness assessment and pharmacokinetics profiling

The drug-likeness of the hit compounds of this study was assessed based on the Ro5 to determine their viability to serve as orally active drugs in humans. As evident in Table 2, none of the hit compounds of this study violated the Ro5; hence, they are all drug-like.

Table 2

The physicochemical properties of the hit compounds based on the Ro5

Compound MW (Da) NHBA NHBD MLOGP Violations
135964525 437.86 6 1 3.21 0
44130718 395.34 6 0 3.53 0
135438537 437.40 9 2 2.96 0
135505656 423.83 7 2 3.22 0
135520508 464.41 10 2 1.93 0
Methicillin 380.42 6 2 1.06 0

The ADMET properties of the hit compounds are also presented in Table 3. All the compounds possessed higher intestinal absorption potentials compared to methicillin; however, they all possess the potential to inhibit P-glycoprotein I and II (Table 3). Disappointingly, three of the compounds which are “135438537,” “135505656,” and “135520508” were predicted to be AMES toxic.

Table 3

The drug-likeness profile and pharmacokinetics properties of the hit compounds of this study

Models Compounds
135964525 44130718 135438537 135505656 135520508 Methicillin
Absorption
HIA 100 57.839 93.029 93.827 86.196 45.343
Water solubility −4.278 −2.992 0.583 0.679 −3.352 −2.628
Caco-2 permeability 1.023 0.993 −3.236 −3.143 0.45 0.563
P-gp (substrate) Non-substrate Substrate Substrate Substrate Substrate Substrate
P-gp I (inhibitor) Inhibitor Non-inhibitor Inhibitor Inhibitor Inhibitor Non-inhibitor
P-gp II (inhibitor) Inhibitor Non-inhibitor Inhibitor Inhibitor Inhibitor Non-inhibitor
Distribution
Fraction unbound 0 0.245 0 0 0.022 −1.62
Metabolism
CYP450 2C9 (inhibition) Inhibitor Non-inhibitor Non-inhibitor Inhibitor Inhibitor Non-inhibitor
CYP450 2D6 (substrate) Non-substrate Non-substrate Non-substrate Non-substrate Non-substrate Non-substrate
CYP450 2D6 (inhibition) Non-inhibitor Non-inhibitor Non-inhibitor Non-inhibitor Non-inhibitor Non-inhibitor
CYP450 3A4 (substrate) Substrate Non-substrate Substrate Non-substrate Substrate Non-substrate
CYP450 3A4 (inhibition) Inhibitor Non-inhibitor Inhibitor Non-inhibitor Inhibitor Non-inhibitor
CYP450 1A2 (inhibition) Non-Inhibitor Non-inhibitor Non-Inhibitor Inhibitor Non-Inhibitor Non-Inhibitor
CYP450 2C19 (inhibition) Inhibitor Non-inhibitor Inhibitor Non-inhibitor Non-inhibitor Non-inhibitor
Excretion
Renal organic cation transporter 2 (OCT2) Non-substrate Non-substrate Non-substrate Non-substrate Non-substrate Non-substrate
Toxicity
AMES toxicity Non-toxic Non-toxic Toxic Toxic Toxic Non-toxic
hERG I inhibitor Non-inhibitor Non-inhibitor Non-inhibitor Non-inhibitor Inhibitor Non-inhibitor
Skin sensitization No No No No No No

3.5 All atoms MD simulation of the final complexes

As evident in Figure 3, the complexes formed by the individual compound with the best docking scores for FemA and PBP-2a, as well as the complexes formed by the standard drug (methicillin) were selected for MD simulation, the complexes are PBP-2a_Methicillin and PBP-2a_44130718, and FemA_methicillin and FemA_135964525 complexes.

Figure 3 RMSD analysis of FemA complexes over a 250 ns simulation period. (a) The RMSD graph of FemA_Apo, FemA_methicillin, and FemA_135964525 complexes. (b) The RMSD of PBP-2a_Apo, PBP-2a_Methicillin (control), and PBP-2a_44130718 complexes.
Figure 3

RMSD analysis of FemA complexes over a 250 ns simulation period. (a) The RMSD graph of FemA_Apo, FemA_methicillin, and FemA_135964525 complexes. (b) The RMSD of PBP-2a_Apo, PBP-2a_Methicillin (control), and PBP-2a_44130718 complexes.

3.5.1 Dynamic stability assessment analysis

The RMSD of the FemA apoprotein (FemA_Apo), FemA_methicillin, and FemA_135964525 during the 250 ns simulation period are depicted in Figure 3a, while that of PBP-2a apoprotein (PBP-2a_Apo), PBP-2a_methicillin, and PBP-2a_44130718 are presented in Figure 3b.

3.5.2 Protein residual flexibility analysis

The RMSF of the FemA apoprotein (FemA_Apo), FemA_methicillin, and FemA_135964525 during the 250 ns simulation period are depicted in Figure 4a, while that of PBP-2a apoprotein (PBP-2a_Apo), PBP-2a_methicillin, and PBP-2a_44130718 are presented in Figure 4b.

Figure 4 Residual flexibility result of final complexes. (a) The RMSF results for the FemA_Apo, FemA_methicillin (control) and FemA_135964525 (b) PBP-2a_Apo, PBP-2a_Methicillin (control) and PBP-2a_44130718.
Figure 4

Residual flexibility result of final complexes. (a) The RMSF results for the FemA_Apo, FemA_methicillin (control) and FemA_135964525 (b) PBP-2a_Apo, PBP-2a_Methicillin (control) and PBP-2a_44130718.

3.5.3 Assessment of structural packing and residue flexibility

The radius of gyration, or structural packing, is a key metric for assessing protein size variation throughout the simulation time. It also provides crucial insights into the stability of the protein. Furthermore, this method has been significantly used to detect the binding and unbinding events throughout the simulation. The radius of gyration plots for the complexes are depicted in Figure 5(a) and (b).

Figure 5 Radius of gyration result of final complexes. (a) The Rg results for the FemA_Apo, FemA_methicillin (control) and FemA_135964525 and (b) PBP-2a_Apo, PBP-2a_Methicillin (control) and PBP-2a_44130718.
Figure 5

Radius of gyration result of final complexes. (a) The Rg results for the FemA_Apo, FemA_methicillin (control) and FemA_135964525 and (b) PBP-2a_Apo, PBP-2a_Methicillin (control) and PBP-2a_44130718.

3.5.4 Hydrogen bonding analysis

The persistence of the hydrogen bond over 250 ns simulation was plotted and is depicted in Figure 6.

Figure 6 The persistence of the hydrogen bond over 250 ns simulation was plotted and is depicted in Figures 6a and b.
Figure 6

The persistence of the hydrogen bond over 250 ns simulation was plotted and is depicted in Figures 6a and b.

3.5.5 Per-residues energy decomposition analysis

To assess the impact of each residue and its contribution to the total binding energy, a per-residue energy decomposition analysis was performed on the trajectory file obtained from the 250 ns simulation and the results are depicted in Figure 7.

Figure 7 The figure showing energy per-residue energy decomposition analysis contributing to the total energy. All the energies are given in kcal/mol.
Figure 7

The figure showing energy per-residue energy decomposition analysis contributing to the total energy. All the energies are given in kcal/mol.

3.5.6 Binding free energy calculations

Free energy computation and analysis were conducted to quantitatively compare the interaction changes between the control drug and the designed drug systems. A total of 5,000 snapshots from the last 250 ns of the MD simulation trajectory were used to calculate the total free energy. Each contributing term, including vdW, electrostatic, polar solvation, and SASA energies, was calculated and is presented in Table 4 (MM/GBSA). The MM/GBSA results also show variations in energies between the control drug and the hit compounds, with the most significant differences observed in total and electrostatic energies.

Table 4

MM/PBSA of wild-type and mutant systems

Complex name MMPBSA (kJ/mol)
Δ vdW Δ elec Δ ps Δ G,total
1LRZ_methicillin −31.28 ± 12.66 −1317.27 ± 94.28 1227.43 ± 169.48 −35.41 ± 35.11
1LRZ_135964525 −53.88 ± 11.13 −1501.34 ± 100.01 1691.063 ± 109.13 −42.54 ± 12.30
5M18_Methicillin −42.58 ± 16.14 −1103.16 ± 101.35 1180.23 ± 98.691 −31.01 ± 12.21
5M18_44130718 −53.56 ± 11.63 −1501.61 ± 131.16 1512.22 ± 83.58 −35.41 ± 11.20

4 Discussion

Globally, the treatment of S. aureus has become challenging due to the emergence of resistant strains; hence, the search for alternative drugs that can be used in its treatment is ongoing. In this study, 72 compounds were virtually screened to evaluate their potential as inhibitors of two crucial MRSA proteins.

A semi-flexible docking methodology revealed that the selected hit compounds exhibited high affinity for the targets, with docking scores ranging from −8.6 to −10.1 kcal/mol for PBP-2a and from −9.6 to −9.9 kcal/mol for FemA. In this study, we applied two different exhaustiveness values, “8” and “32.” The exhaustiveness parameter in AutoDock Vina controls the depth and thoroughness of the conformational search for optimal ligand binding poses. The default exhaustiveness value in AutoDock Vina is “8,” and it provides a balance between computational efficiency and search thoroughness. This setting allowed us to perform initial screenings rapidly while maintaining reasonable accuracy in identifying potential binding poses. However, increasing the exhaustiveness to 32 significantly enhanced the thoroughness of the conformational search. Although this higher setting required more computational resources and time, it resulted in a more detailed exploration of the ligand binding space, hence, improving the reliability of our docking results and enabling a more precise identification of the best binding poses and interactions. Interestingly, a study by Agarwal and Smith, in which they evaluated the effect of box sizes and exhaustiveness values on AutoDock Vina-generated ligand pose accuracy, reported that utilizing the default exhaustiveness value will likely lead to the generation of false positive results, while values greater than 25 have minimal contribution to the quality of the results at the expense of computational time [39]. Hence, it can be concluded that the value utilized in this study gives the best results that can be obtained using AutoDock Vina.

The hit compounds of this study interacted with relevant amino acid residues of PBP-2a. The compound with the CID “135964525” formed hydrogen bonds with LYS148 and GLN292, and formed Van der Waals interactions with THR165, SER240, ARG241, GLY271, TYR272, and GLU294. It also formed pi-sulfur interaction with HIS293, pi-donor interactions with GLU239 and LYS273, pi-anion interaction with ASP275, and pi-alkyl interaction with ALA276. Similarly, compound “44130718” formed two hydrogen bonds with GLU239 and ARG241, vdW interaction with LYS148, GLU150, THR165, SER240, VAL256, GLY257, PRO258, HIS293, MET372, and TYR373, formed pi-alkyl with ARG151 and VAL277. Compound “135425237” formed hydrogen bond with GLU239, ASP275, and VAL277; pi-sulfur interaction with HIS293; pi-sigma interaction with ALA276; vdW interaction with LYS148, THR165, SER240, VAL256, GLY271, TYR272, GLU294, and ASP295; and carbon hydrogen bond with ARG151 and ARG241. Compound “135505656” formed hydrogen bond with ASP275, GLN292, and HIS293; vdW interaction THR165, GLU239, GLY271, TYR272, and GLU294; pi-donor interaction with VAL277; pi-sigma interaction with ALA276; and pi-alkyl interaction with ARG151, ARG241, and LYS273. Compound “135520508” formed two hydrogen bonds with ASP275 and one hydrogen bond with GLN292 and HIS293; vdW interaction with THR165, GLU239, ARG241, VAL256, GLY271, LYS289, and GLU294; pi-cation interaction with LYS148; pi-donor interaction with VAL277; pi-sigma interaction with ALA276; and pi-alkyl interactions with ARG151, TYR272, and LYS273. The standard drug (methicillin) formed hydrogen bonds with LYS148 and GLN292; vdW interactions with SER149, GLU150, ARG151, THR216, THR238, GLU239, SER240, VAL256, GLY257, PRO258, VAL277, and TYR373; carbon–hydrogen bond with THR165; pi–pi T-shaped with HIS293; and pi–pi alkyl interaction with LYS148. It is worth noting that the interactions of these compounds are with the allosteric site residues of PBP-2a, which control the activity of the active site of the protein [23], and the residues with which they interacted were similar to those reported by Aribisala and Sabiu for their hit compounds [40].

The interaction of the hit compounds with FemA also included hydrogen bond interactions among others. The compound “135425237” interacted with FemA via hydrogen bond with THR332 and GLY365; vdW interactions with PHE149, MET208, TYR328, ALA329, GLY330, GLY331, ARG337, and SER342; pi-sulfur interactions with TYR327; pi-cation interaction with LYS383; halogen-based interaction with GLY378; and alkyl and pi-alkyl interactions with ILE165, VAL379, and PHE382. Compound “44130718” formed hydrogen bonds with TYR20, TYR115, and ASP162; carbon–hydrogen bond with GLU81; vdW interactions TYR80, LEU111, ALA126, VAL160, LYS164, PHE323, ASP359, GLU389, and ILE391; pi-donor interactions with ARG36 and ASP162; pi-alkyl interaction with PRO19 and PRO112; pi–pi T-shaped interaction with TYR20; and an unfavorable donor–donor interaction with ASN128. Compound “135505656” formed just one hydrogen bond with THR332; vdW interactions with GLY330, GLY331, ARG337, SER342, PHE363, GLY365, VAL366, ASP376, and LYS383; pi-sulfur interaction with TYR327; pi–pi stacked interaction with PHE149; two pi-alkyl interactions with VAL379 and another with PHE382; and an alkyl interaction with VAL379. Compound “135520508” formed hydrogen bonds with TYR327, GLY330, SER342, GLY365 and two hydrogen bond interactions with TYR328; vdW interactions with PHE149, LEU153, MET208, ALA329, ARG337, GLN346, TYR364, and PHE382; pi-sigma interactions with ILE155 and VAL379; and pi–pi T-shaped interaction with TYR328. Compound “135964525” interacted with GLY330 and GLY365; vdW interactions with TYR328, GLY331, SER342, LYS383; pi-donor hydrogen bond with TYR327; pi–pi stacked interactions with PHE149 and PHE382; pi-alkyl interactions with PHE149 and VAL379; and alkyl interactions with ILE155, TYR364, PHE382, and VAL379. Methicillin formed a hydrogen bond with LYS383; vdW interactions with TYR328, GLY330, GLY331, ARG337, SER342, GLN346, GLY365, and ASP376; pi–pi T-shaped interaction with PHE382; pi-alkyl interaction with VAL379; and alkyl interactions with PHE149, TYR327, VAL379, and PHE382. The 1B domain of FemA has been reported as the only active site of the protein. Interestingly, the hit compounds of this study interacted with the residues reported by Rahman and Das as being present in this domain [41].

All the hit compounds were predicted to be drug-like, showcasing their potential to serve as oral drugs. Noteworthy, the Ro5 is a widely utilized guideline in drug discovery to predict the likelihood of a compound possessing good oral bioavailability [29]. It is employed in the initial stages of drug discovery and it stipulates that a compound should possess a molecular weight below 500 Da, have no more than five hydrogen bond donors, have no more than ten hydrogen bond acceptors, and maintain an octanol-water partition coefficient value below 5. The hit compounds of this study did not violate any of these parameters, hence, their potential viability as orally administered therapeutic agents.

Also, all the compounds exhibited high HIA potential compared to methicillin. Conversely, the Caco-2 permeability potential was high for compounds “135964525” and “44130718,” moderate for “135520508” and “methicillin,” but very poor for “135438537” and “135505656.” The discrepancies observed between the predictions of HIA and Caco-2 permeability can be attributed to several underlying factors. A primary contributor to these divergent outcomes is the differences between the cellular models employed. While Caco-2 cells, derived from human colon carcinoma, are widely utilized as an in vitro model to approximate intestinal absorption, they fail to fully model the diverse conditions and cell types present within the human intestinal environment [42]. Moreover, certain compounds may undergo efficient absorption in the human intestine facilitated by active transport mechanisms that are either absent or not widely expressed in Caco-2 cells. Notably, peptide transporters such as PEPT1 and PEPT2, along with other specific transport proteins, can significantly enhance intestinal absorption, yet their functionality in the Caco-2 cell line may not be efficient [43]. Furthermore, the statistical models employed in these analyses are trained on distinct datasets, contributing to the observed variations in their predictive outcomes [31]. Among the compounds, only “135964525” was predicted to be a non-substrate of the P-gp, while “44130718” and methicillin were the non-inhibitors of P-gp I and II. P-gp, an efflux transporter expressed across various tissues in the body, plays a pivotal role in regulating the cellular uptake and distribution of xenobiotic and potentially harmful compounds [44]. Owing to its function as an efflux pump, a compound’s potential to serve as a substrate for P-gp can adversely impact its pharmacokinetic profile and overall therapeutic efficacy. The results of this study show all the hit compounds except “135964525” may require higher dosages to attain the desired therapeutic effects, as their active efflux could result in reduced intracellular drug concentrations. The inhibition of P-gp can result in significant drug-drug interactions by inducing the accumulation of other drugs reliant on P-gp for excretion, potentially leading to toxicity or compromised efficacy [45]. The potential of “44130718” to function as a P-gp inhibitor could lead to toxicity if co-administered with other drugs reliant on P-gp for excretion. As regards the distribution of the hit compounds, the fraction unbound of all the compounds except “44130718” was very low. Drugs can bind to plasma proteins such as albumin and alpha-1-acid glycoprotein, resulting in a reduced pharmacological form [46]. Specifically, the fraction unbound is essential for understanding a drug’s pharmacokinetics and pharmacodynamics, as only the unbound drug fraction is available to exert therapeutic effects. Despite the observed high affinities of “135964525,” “135438537,” and “135505656,” their utilization will be greatly limited due to their predicted fraction unbound values. In terms of drug metabolism, the inhibition of cytochrome P450 (CYP450) enzymes plays a critical role in modulating metabolic processes by lowering the enzymatic reaction rates. This phenomenon can decrease the metabolism of drugs, thereby influencing potential drug interactions that affect treatment efficacy and may elevate the occurrence of adverse effects [47]. All the hit compounds were non-substrate and non-inhibitors of CYP2D6 and non-inhibitors of CYP1A2 and CYP2C19, except for “135505656” which can potentially inhibit CYP1A2. As regards excretion, OCT2 plays a significant role in the pharmacokinetics and pharmacodynamics of various drugs by mediating their uptake into renal tubular cells, affecting their excretion and overall disposition. It is predominantly expressed in the basolateral membrane of renal proximal tubules where it facilitates the uptake of endogenous compounds and exogenous substances, including drugs, from the bloodstream into renal cells for subsequent excretion [48]. Drugs that are not substrates for OCT2 may have a longer systemic circulation time and slower renal elimination. This can be beneficial for drugs requiring sustained therapeutic levels or for drugs with a narrow therapeutic index [49]. The inability of all the hit compounds to serve as substrates of OCT2 will potentially constitute an advantage for the compounds due to their low fraction unbound, therefore, helping them achieve prolonged therapeutic effect. Disappointingly, three of the hit compounds exhibited bad safety profiles as they possess the potential to cause mutagenesis, and may cause carcinogenesis [50].

As evident in Figure 3a, the FemA_Apo complex exhibited the least deviation compared to that of the control and the final hits, with an average RMSD of 0.325 ± 2.041 Å. Conversely, the FemA_methicillin complex exhibited an average RMSD of 0.695 ± 3.008 Å, while that of the FemA_135964525 complex was 0.508 ± 1.553 Å. The PBP-2a_Apo complex also recorded minimal RMSD fluctuations compared to the control, with an average RMSD of 0.805 ± 1.072 Å (Figure 3b). The 5M18_44130718 complex maintained a uniform RMSD level and demonstrated the most stable behavior among the complexes. Notably, the PBP-2a_Methicillin (control) complex initially exhibited similar RMSD levels to the 5M18_44130718 complex; however, significant structural deviations were observed between 150 and 200 ns. Similarly, the Apo state of the PBP-2a protein showed consistent levels with minimal deviations, demonstrating a stable structural conformation throughout the simulation period.

In the FemA_Apo protein, the regions between residues 50–80 and 280–300 exhibited fluctuation, with the RMSF value of the 50–80th residues increasing from 7 to 14 Å, while the 280–290th residues showed changes in RMSF to 11 Å, which later reduced to less an average of 2 Å for the remaining. The residues at the termini region of the hit complexes exhibited the highest flexibility, with RMSF value as high as 12.5 Å for FemA_135964525 complex as opposed to the 8 Å for FemA_135964525. The fluctuation of the residues was relatively stable except for the amino acid residues between 220 and 270 which had a high fluctuation. Conversely, the PBP-2a_Methicillin complex residues had higher fluctuation compared to the PBP-2a_44130718 residues. The complexes’ residues between 1 and 380 had similar fluctuation profiles, however, the PBP-2a_Methicillin residues at 380 residues and above had a highly unstable fluctuation compared to the hit compound’s complexes. These RMSF profiles serve as indicators of structural differences between the control complexes and their respective counterparts, with lower values suggesting greater structural similarity and higher values indicating increased structural divergence.

As evident in Figure 5(a) and (b), all the complexes strongly align with the RMSD results and demonstrated similar levels of Rg, thus showing the same level of protein size during the simulation. The first peak in our Radius of Gyration analysis corresponds to the control complex FemA_methicillin. The calculated Rg value for this complex, 27.3 Å, indicates its compactness and overall structural stability. A lower Rg value for this peak suggests that the control complex maintains a well-folded and comparatively compact conformation. This structural stability is crucial for the normal functioning of the complex. Moving to the second peak, which represents the FemA_135964525, the Rg value of 36.4 Å provides insights into its size and shape compared to the control. A detailed analysis of this peak suggests that FemA_135964525 may exhibit structural differences when compared to the control, potentially indicating a change in its conformational flexibility or compactness. These results are strongly in tandem with the RMSD results thus maintaining a similar level with no significant deviation. This further demonstrates minimal or no unbinding events experienced by the ligand during the simulation.

In the interaction of small molecules with biological targets, the importance of hydrogen bonds cannot be overlooked, due to the role it plays in determining the affinity and specificity of the compounds. Hence, the stability of the hydrogen bonds formed between the complexes was investigated over the 250 ns simulation period. As evident in Figure 6, the average hydrogen bonds in FemA_135964525, and PBP-2a_44130718 complexes remained higher than the control drug. For instance, the PBP-2a_44130718 exhibited the highest number of hydrogen bonds, with about 7 hydrogen bonds between the ligand and receptor during the simulations. The results shown in Figure 7, demonstrate that our identified hits may strongly inhibit the function of the proteins than the control drug.

The energy decomposition analysis graph describes the total interaction of each residue in drug to binding free with respect target protein. These results reveal important insights into how peptide-drug interactions. Per-residue energy decomposition analysis was conducted on the 250 ns simulation trajectory, revealing the individual residue contributions to the total energy for each system, as illustrated in Figure 7. As evident in Figure 7, it is evident that Tyr327, Ser149, Arg139, Gln292, and Gln292 significantly contributed to the total energy while the other residues such as Phe363, Lys383, Lys148, Glu150, Thr165, Arg24, Val256, Gly271, Lys289 and also contributed to the total energy.

The MMPBSA analysis reveals significant insights into the binding interactions of various drug-protein complexes. For the 1LRZ_methicillin complex, the total binding free energy (Δ G,Total) is −35.41 ± 35.11 kJ/mol, with considerable contributions from vdW (Δ vdW) and electrostatic (Δ elec) interactions. In contrast, the 1LRZ_135964525 complex exhibits a more favorable binding affinity (Δ G,Total = −42.54 ± 12.30 kJ/mol) due to higher vdW and electrostatic contributions, despite a higher polar solvation energy (Δ ps). Similarly, the 5M18_Methicillin complex shows a Δ G,total of −31.01 ± 12.21 kJ/mol, indicating slightly less favorable binding compared to the 1LRZ_methicillin complex, but still driven by strong vdW and electrostatic forces.

The 5M18_44130718 complex, with a Δ G,total of −35.41 ± 11.20 kJ/mol, demonstrates substantial vdW and electrostatic contributions, comparable to the 1LRZ_135964525 complex. These results underscore the critical role of vdW and electrostatic interactions in stabilizing the drug-protein complexes, while variations in polar solvation energy highlight the importance of solvation effects in modulating binding affinities. Overall, the analysis suggests that ligands 135964525 and 44130718 have stronger binding affinities compared to methicillin, offering valuable insights for optimizing drug candidates.

5 Conclusion

In conclusion, this study highlights the potential of two compounds as treatment for MRSA by targeting two key proteins, PBP-2a and FemA. The semi-flexible docking methodology demonstrated that the hit compounds exhibited high affinity for the targets, with notable interactions at crucial binding sites. Furthermore, the compounds’ drug-likeness, high human intestinal absorption potential, and favorable interaction profiles with key residues in PBP-2a and FemA, suggest their viability as complementary therapeutic agents. The MD simulations and energy decomposition analyses provided deeper insights into the stability and binding interactions, reinforcing the potential of these compounds to serve as effective alternatives to traditional antibiotics in the fight against MRSA.

Acknowledgements

The authors extend their appreciation to the Researchers Supporting Project number (RSP2024R437), King Saud University, Riyadh, Saudi Arabia.

  1. Funding information: This work is supported by the Researchers Supporting Project number (RSP2024R437), King Saud University, Riyadh, Saudi Arabia.

  2. Author contributions: Conceptualization, writing the original draft, formal analysis: Mohammed Bourhia, Muhammad Shahab, and Guojun Zheng. Investigations, funding acquisition, resources, and project administration: Mohamed Taibi, Amine Elbouzidi, Musaab Dauelbait. Reviewing and editing, data validation, and data curation and supervision: Ahmad Mohammad Salamatullah and Abdeslam Asehraou.

  3. Conflict of interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

  4. Ethical approval: The conducted research is not related to either human or animals use.

  5. Data availability statement: Data will be available upon request from the corresponding author.

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Received: 2024-04-13
Revised: 2024-08-02
Accepted: 2024-08-18
Published Online: 2024-10-02

© 2024 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Regular Articles
  2. Porous silicon nanostructures: Synthesis, characterization, and their antifungal activity
  3. Biochar from de-oiled Chlorella vulgaris and its adsorption on antibiotics
  4. Phytochemicals profiling, in vitro and in vivo antidiabetic activity, and in silico studies on Ajuga iva (L.) Schreb.: A comprehensive approach
  5. Synthesis, characterization, in silico and in vitro studies of novel glycoconjugates as potential antibacterial, antifungal, and antileishmanial agents
  6. Sonochemical synthesis of gold nanoparticles mediated by potato starch: Its performance in the treatment of esophageal cancer
  7. Computational study of ADME-Tox prediction of selected phytochemicals from Punica granatum peels
  8. Phytochemical analysis, in vitro antioxidant and antifungal activities of extracts and essential oil derived from Artemisia herba-alba Asso
  9. Two triazole-based coordination polymers: Synthesis and crystal structure characterization
  10. Phytochemical and physicochemical studies of different apple varieties grown in Morocco
  11. 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
  12. Nutraceutical potential of Mesembryanthemum forsskaolii Hochst. ex Bioss.: Insights into its nutritional composition, phytochemical contents, and antioxidant activity
  13. Evaluation of influence of Butea monosperma floral extract on inflammatory biomarkers
  14. Cannabis sativa L. essential oil: Chemical composition, anti-oxidant, anti-microbial properties, and acute toxicity: In vitro, in vivo, and in silico study
  15. The effect of gamma radiation on 5-hydroxymethylfurfural conversion in water and dimethyl sulfoxide
  16. Hollow mushroom nanomaterials for potentiometric sensing of Pb2+ ions in water via the intercalation of iodide ions into the polypyrrole matrix
  17. Determination of essential oil and chemical composition of St. John’s Wort
  18. Computational design and in vitro assay of lantadene-based novel inhibitors of NS3 protease of dengue virus
  19. Anti-parasitic activity and computational studies on a novel labdane diterpene from the roots of Vachellia nilotica
  20. Microbial dynamics and dehydrogenase activity in tomato (Lycopersicon esculentum Mill.) rhizospheres: Impacts on growth and soil health across different soil types
  21. Correlation between in vitro anti-urease activity and in silico molecular modeling approach of novel imidazopyridine–oxadiazole hybrids derivatives
  22. Spatial mapping of indoor air quality in a light metro system using the geographic information system method
  23. Iron indices and hemogram in renal anemia and the improvement with Tribulus terrestris green-formulated silver nanoparticles applied on rat model
  24. Integrated track of nano-informatics coupling with the enrichment concept in developing a novel nanoparticle targeting ERK protein in Naegleria fowleri
  25. Cytotoxic and phytochemical screening of Solanum lycopersicum–Daucus carota hydro-ethanolic extract and in silico evaluation of its lycopene content as anticancer agent
  26. Protective activities of silver nanoparticles containing Panax japonicus on apoptotic, inflammatory, and oxidative alterations in isoproterenol-induced cardiotoxicity
  27. pH-based colorimetric detection of monofunctional aldehydes in liquid and gas phases
  28. Investigating the effect of resveratrol on apoptosis and regulation of gene expression of Caco-2 cells: Unravelling potential implications for colorectal cancer treatment
  29. Metformin inhibits knee osteoarthritis induced by type 2 diabetes mellitus in rats: S100A8/9 and S100A12 as players and therapeutic targets
  30. Effect of silver nanoparticles formulated by Silybum marianum on menopausal urinary incontinence in ovariectomized rats
  31. Synthesis of new analogs of N-substituted(benzoylamino)-1,2,3,6-tetrahydropyridines
  32. Response of yield and quality of Japonica rice to different gradients of moisture deficit at grain-filling stage in cold regions
  33. Preparation of an inclusion complex of nickel-based β-cyclodextrin: Characterization and accelerating the osteoarthritis articular cartilage repair
  34. Empagliflozin-loaded nanomicelles responsive to reactive oxygen species for renal ischemia/reperfusion injury protection
  35. Preparation and pharmacodynamic evaluation of sodium aescinate solid lipid nanoparticles
  36. Assessment of potentially toxic elements and health risks of agricultural soil in Southwest Riyadh, Saudi Arabia
  37. Theoretical investigation of hydrogen-rich fuel production through ammonia decomposition
  38. Biosynthesis and screening of cobalt nanoparticles using citrus species for antimicrobial activity
  39. Investigating the interplay of genetic variations, MCP-1 polymorphism, and docking with phytochemical inhibitors for combatting dengue virus pathogenicity through in silico analysis
  40. Ultrasound induced biosynthesis of silver nanoparticles embedded into chitosan polymers: Investigation of its anti-cutaneous squamous cell carcinoma effects
  41. Copper oxide nanoparticles-mediated Heliotropium bacciferum leaf extract: Antifungal activity and molecular docking assays against strawberry pathogens
  42. Sprouted wheat flour for improving physical, chemical, rheological, microbial load, and quality properties of fino bread
  43. Comparative toxicity assessment of fisetin-aided artificial intelligence-assisted drug design targeting epibulbar dermoid through phytochemicals
  44. Acute toxicity and anti-inflammatory activity of bis-thiourea derivatives
  45. Anti-diabetic activity-guided isolation of α-amylase and α-glucosidase inhibitory terpenes from Capsella bursa-pastoris Linn.
  46. GC–MS analysis of Lactobacillus plantarum YW11 metabolites and its computational analysis on familial pulmonary fibrosis hub genes
  47. Green formulation of copper nanoparticles by Pistacia khinjuk leaf aqueous extract: Introducing a novel chemotherapeutic drug for the treatment of prostate cancer
  48. Improved photocatalytic properties of WO3 nanoparticles for Malachite green dye degradation under visible light irradiation: An effect of La doping
  49. 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
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  51. A comparative study of the antifungal efficacy and phytochemical composition of date palm leaflet extracts
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  58. 3D-QSAR, molecular docking, ADMET, simulation dynamic, and retrosynthesis studies on new styrylquinolines derivatives against breast cancer
  59. Deciphering the influenza neuraminidase inhibitory potential of naturally occurring biflavonoids: An in silico approach
  60. Determination of heavy elements in agricultural regions, Saudi Arabia
  61. Synthesis and characterization of antioxidant-enriched Moringa oil-based edible oleogel
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https://doi.org/10.1515/chem-2024-0082
Keywords for this article
methicillin-resistance; Staphylococcus aureus; napthyridine compound; oxadiazoles compound; PBP-2a protein; FemA protein
Creative Commons
BY 4.0

Articles in the same Issue

  1. Regular Articles
  2. Porous silicon nanostructures: Synthesis, characterization, and their antifungal activity
  3. Biochar from de-oiled Chlorella vulgaris and its adsorption on antibiotics
  4. Phytochemicals profiling, in vitro and in vivo antidiabetic activity, and in silico studies on Ajuga iva (L.) Schreb.: A comprehensive approach
  5. Synthesis, characterization, in silico and in vitro studies of novel glycoconjugates as potential antibacterial, antifungal, and antileishmanial agents
  6. Sonochemical synthesis of gold nanoparticles mediated by potato starch: Its performance in the treatment of esophageal cancer
  7. Computational study of ADME-Tox prediction of selected phytochemicals from Punica granatum peels
  8. Phytochemical analysis, in vitro antioxidant and antifungal activities of extracts and essential oil derived from Artemisia herba-alba Asso
  9. Two triazole-based coordination polymers: Synthesis and crystal structure characterization
  10. Phytochemical and physicochemical studies of different apple varieties grown in Morocco
  11. 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
  12. Nutraceutical potential of Mesembryanthemum forsskaolii Hochst. ex Bioss.: Insights into its nutritional composition, phytochemical contents, and antioxidant activity
  13. Evaluation of influence of Butea monosperma floral extract on inflammatory biomarkers
  14. Cannabis sativa L. essential oil: Chemical composition, anti-oxidant, anti-microbial properties, and acute toxicity: In vitro, in vivo, and in silico study
  15. The effect of gamma radiation on 5-hydroxymethylfurfural conversion in water and dimethyl sulfoxide
  16. Hollow mushroom nanomaterials for potentiometric sensing of Pb2+ ions in water via the intercalation of iodide ions into the polypyrrole matrix
  17. Determination of essential oil and chemical composition of St. John’s Wort
  18. Computational design and in vitro assay of lantadene-based novel inhibitors of NS3 protease of dengue virus
  19. Anti-parasitic activity and computational studies on a novel labdane diterpene from the roots of Vachellia nilotica
  20. Microbial dynamics and dehydrogenase activity in tomato (Lycopersicon esculentum Mill.) rhizospheres: Impacts on growth and soil health across different soil types
  21. Correlation between in vitro anti-urease activity and in silico molecular modeling approach of novel imidazopyridine–oxadiazole hybrids derivatives
  22. Spatial mapping of indoor air quality in a light metro system using the geographic information system method
  23. Iron indices and hemogram in renal anemia and the improvement with Tribulus terrestris green-formulated silver nanoparticles applied on rat model
  24. Integrated track of nano-informatics coupling with the enrichment concept in developing a novel nanoparticle targeting ERK protein in Naegleria fowleri
  25. Cytotoxic and phytochemical screening of Solanum lycopersicum–Daucus carota hydro-ethanolic extract and in silico evaluation of its lycopene content as anticancer agent
  26. Protective activities of silver nanoparticles containing Panax japonicus on apoptotic, inflammatory, and oxidative alterations in isoproterenol-induced cardiotoxicity
  27. pH-based colorimetric detection of monofunctional aldehydes in liquid and gas phases
  28. Investigating the effect of resveratrol on apoptosis and regulation of gene expression of Caco-2 cells: Unravelling potential implications for colorectal cancer treatment
  29. Metformin inhibits knee osteoarthritis induced by type 2 diabetes mellitus in rats: S100A8/9 and S100A12 as players and therapeutic targets
  30. Effect of silver nanoparticles formulated by Silybum marianum on menopausal urinary incontinence in ovariectomized rats
  31. Synthesis of new analogs of N-substituted(benzoylamino)-1,2,3,6-tetrahydropyridines
  32. Response of yield and quality of Japonica rice to different gradients of moisture deficit at grain-filling stage in cold regions
  33. Preparation of an inclusion complex of nickel-based β-cyclodextrin: Characterization and accelerating the osteoarthritis articular cartilage repair
  34. Empagliflozin-loaded nanomicelles responsive to reactive oxygen species for renal ischemia/reperfusion injury protection
  35. Preparation and pharmacodynamic evaluation of sodium aescinate solid lipid nanoparticles
  36. Assessment of potentially toxic elements and health risks of agricultural soil in Southwest Riyadh, Saudi Arabia
  37. Theoretical investigation of hydrogen-rich fuel production through ammonia decomposition
  38. Biosynthesis and screening of cobalt nanoparticles using citrus species for antimicrobial activity
  39. Investigating the interplay of genetic variations, MCP-1 polymorphism, and docking with phytochemical inhibitors for combatting dengue virus pathogenicity through in silico analysis
  40. Ultrasound induced biosynthesis of silver nanoparticles embedded into chitosan polymers: Investigation of its anti-cutaneous squamous cell carcinoma effects
  41. Copper oxide nanoparticles-mediated Heliotropium bacciferum leaf extract: Antifungal activity and molecular docking assays against strawberry pathogens
  42. Sprouted wheat flour for improving physical, chemical, rheological, microbial load, and quality properties of fino bread
  43. Comparative toxicity assessment of fisetin-aided artificial intelligence-assisted drug design targeting epibulbar dermoid through phytochemicals
  44. Acute toxicity and anti-inflammatory activity of bis-thiourea derivatives
  45. Anti-diabetic activity-guided isolation of α-amylase and α-glucosidase inhibitory terpenes from Capsella bursa-pastoris Linn.
  46. GC–MS analysis of Lactobacillus plantarum YW11 metabolites and its computational analysis on familial pulmonary fibrosis hub genes
  47. Green formulation of copper nanoparticles by Pistacia khinjuk leaf aqueous extract: Introducing a novel chemotherapeutic drug for the treatment of prostate cancer
  48. Improved photocatalytic properties of WO3 nanoparticles for Malachite green dye degradation under visible light irradiation: An effect of La doping
  49. 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
  50. Groundwater quality and health risk assessment of nitrate and fluoride in Al Qaseem area, Saudi Arabia
  51. A comparative study of the antifungal efficacy and phytochemical composition of date palm leaflet extracts
  52. Processing of alcohol pomelo beverage (Citrus grandis (L.) Osbeck) using saccharomyces yeast: Optimization, physicochemical quality, and sensory characteristics
  53. Specialized compounds of four Cameroonian spices: Isolation, characterization, and in silico evaluation as prospective SARS-CoV-2 inhibitors
  54. Identification of a novel drug target in Porphyromonas gingivalis by a computational genome analysis approach
  55. Physico-chemical properties and durability of a fly-ash-based geopolymer
  56. FMS-like tyrosine kinase 3 inhibitory potentials of some phytochemicals from anti-leukemic plants using computational chemical methodologies
  57. Wild Thymus zygis L. ssp. gracilis and Eucalyptus camaldulensis Dehnh.: Chemical composition, antioxidant and antibacterial activities of essential oils
  58. 3D-QSAR, molecular docking, ADMET, simulation dynamic, and retrosynthesis studies on new styrylquinolines derivatives against breast cancer
  59. Deciphering the influenza neuraminidase inhibitory potential of naturally occurring biflavonoids: An in silico approach
  60. Determination of heavy elements in agricultural regions, Saudi Arabia
  61. Synthesis and characterization of antioxidant-enriched Moringa oil-based edible oleogel
  62. Ameliorative effects of thistle and thyme honeys on cyclophosphamide-induced toxicity in mice
  63. Study of phytochemical compound and antipyretic activity of Chenopodium ambrosioides L. fractions
  64. Investigating the adsorption mechanism of zinc chloride-modified porous carbon for sulfadiazine removal from water
  65. Performance repair of building materials using alumina and silica composite nanomaterials with electrodynamic properties
  66. Effects of nanoparticles on the activity and resistance genes of anaerobic digestion enzymes in livestock and poultry manure containing the antibiotic tetracycline
  67. Effect of copper nanoparticles green-synthesized using Ocimum basilicum against Pseudomonas aeruginosa in mice lung infection model
  68. 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
  69. Anti-OTC antibody-conjugated fluorescent magnetic/silica and fluorescent hybrid silica nanoparticles for oxytetracycline detection
  70. Curcumin conjugated zinc nanoparticles for the treatment of myocardial infarction
  71. Identification and in silico screening of natural phloroglucinols as potential PI3Kα inhibitors: A computational approach for drug discovery
  72. Exploring the phytochemical profile and antioxidant evaluation: Molecular docking and ADMET analysis of main compounds from three Solanum species in Saudi Arabia
  73. 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
  74. Analysis of bioactive compounds present in Boerhavia elegans seeds by GC-MS
  75. Homology modeling and molecular docking study of corticotrophin-releasing hormone: An approach to treat stress-related diseases
  76. LncRNA MIR17HG alleviates heart failure via targeting MIR17HG/miR-153-3p/SIRT1 axis in in vitro model
  77. 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
  78. Biosynthesis of Ag/Cu nanocomposite mediated by Curcuma longa: Evaluation of its antibacterial properties against oral pathogens
  79. Development of AMBER-compliant transferable force field parameters for polytetrafluoroethylene
  80. Treatment of gestational diabetes by Acroptilon repens leaf aqueous extract green-formulated iron nanoparticles in rats
  81. Development and characterization of new ecological adsorbents based on cardoon wastes: Application to brilliant green adsorption
  82. A fast, sensitive, greener, and stability-indicating HPLC method for the standardization and quantitative determination of chlorhexidine acetate in commercial products
  83. Assessment of Se, As, Cd, Cr, Hg, and Pb content status in Ankang tea plantations of China
  84. Effect of transition metal chloride (ZnCl2) on low-temperature pyrolysis of high ash bituminous coal
  85. Evaluating polyphenol and ascorbic acid contents, tannin removal ability, and physical properties during hydrolysis and convective hot-air drying of cashew apple powder
  86. Development and characterization of functional low-fat frozen dairy dessert enhanced with dried lemongrass powder
  87. Scrutinizing the effect of additive and synergistic antibiotics against carbapenem-resistant Pseudomonas aeruginosa
  88. Preparation, characterization, and determination of the therapeutic effects of copper nanoparticles green-formulated by Pistacia atlantica in diabetes-induced cardiac dysfunction in rat
  89. Antioxidant and antidiabetic potentials of methoxy-substituted Schiff bases using in vitro, in vivo, and molecular simulation approaches
  90. Anti-melanoma cancer activity and chemical profile of the essential oil of Seseli yunnanense Franch
  91. Molecular docking analysis of subtilisin-like alkaline serine protease (SLASP) and laccase with natural biopolymers
  92. 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
  93. Exploring novel antitubercular agents: Innovative design of 2,3-diaryl-quinoxalines targeting DprE1 for effective tuberculosis treatment
  94. Drimia maritima flowers as a source of biologically potent components: Optimization of bioactive compound extractions, isolation, UPLC–ESI–MS/MS, and pharmacological properties
  95. 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
  96. Fabrication of β-cyclodextrin-based microgels for enhancing solubility of Terbinafine: An in-vitro and in-vivo toxicological evaluation
  97. Phyto-mediated synthesis of ZnO nanoparticles and their sunlight-driven photocatalytic degradation of cationic and anionic dyes
  98. 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
  99. Quality control analyses of selected honey samples from Serbia based on their mineral and flavonoid profiles, and the invertase activity
  100. 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
  101. Green synthesis of silver nanoparticles containing Cichorium intybus to treat the sepsis-induced DNA damage in the liver of Wistar albino rats
  102. Quality changes of durian pulp (Durio ziberhinus Murr.) in cold storage
  103. Study on recrystallization process of nitroguanidine by directly adding cold water to control temperature
  104. Determination of heavy metals and health risk assessment in drinking water in Bukayriyah City, Saudi Arabia
  105. 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
  106. Design, synthesis, characterization, and theoretical calculations, along with in silico and in vitro antimicrobial proprieties of new isoxazole-amide conjugates
  107. The impact of drying and extraction methods on total lipid, fatty acid profile, and cytotoxicity of Tenebrio molitor larvae
  108. A zinc oxide–tin oxide–nerolidol hybrid nanomaterial: Efficacy against esophageal squamous cell carcinoma
  109. Research on technological process for production of muskmelon juice (Cucumis melo L.)
  110. Physicochemical components, antioxidant activity, and predictive models for quality of soursop tea (Annona muricata L.) during heat pump drying
  111. Characterization and application of Fe1−xCoxFe2O4 nanoparticles in Direct Red 79 adsorption
  112. Torilis arvensis ethanolic extract: Phytochemical analysis, antifungal efficacy, and cytotoxicity properties
  113. 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
  114. HPLC and GC–MS analyses of phytochemical compounds in Haloxylon salicornicum extract: Antibacterial and antifungal activity assessment of phytopathogens
  115. 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
  116. Nitrogen and boron co-doped carbon dots probe for selectively detecting Hg2+ in water samples and the detection mechanism
  117. Heavy metals in road dust from typical old industrial areas of Wuhan: Seasonal distribution and bioaccessibility-based health risk assessment
  118. 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
  119. Investigating dye adsorption: The role of surface-modified montmorillonite nanoclay in kinetics, isotherms, and thermodynamics
  120. Antimicrobial activity, induction of ROS generation in HepG2 liver cancer cells, and chemical composition of Pterospermum heterophyllum
  121. Study on the performance of nanoparticle-modified PVDF membrane in delaying membrane aging
  122. Impact of cholesterol in encapsulated vitamin E acetate within cocoliposomes
  123. Review Articles
  124. Structural aspects of Pt(η3-X1N1X2)(PL) (X1,2 = O, C, or Se) and Pt(η3-N1N2X1)(PL) (X1 = C, S, or Se) derivatives
  125. Biosurfactants in biocorrosion and corrosion mitigation of metals: An overview
  126. Stimulus-responsive MOF–hydrogel composites: Classification, preparation, characterization, and their advancement in medical treatments
  127. Electrochemical dissolution of titanium under alternating current polarization to obtain its dioxide
  128. Special Issue on Recent Trends in Green Chemistry
  129. Phytochemical screening and antioxidant activity of Vitex agnus-castus L.
  130. Phytochemical study, antioxidant activity, and dermoprotective activity of Chenopodium ambrosioides (L.)
  131. Exploitation of mangliculous marine fungi, Amarenographium solium, for the green synthesis of silver nanoparticles and their activity against multiple drug-resistant bacteria
  132. Study of the phytotoxicity of margines on Pistia stratiotes L.
  133. Special Issue on Advanced Nanomaterials for Energy, Environmental and Biological Applications - Part III
  134. Impact of biogenic zinc oxide nanoparticles on growth, development, and antioxidant system of high protein content crop (Lablab purpureus L.) sweet
  135. Green synthesis, characterization, and application of iron and molybdenum nanoparticles and their composites for enhancing the growth of Solanum lycopersicum
  136. Green synthesis of silver nanoparticles from Olea europaea L. extracted polysaccharides, characterization, and its assessment as an antimicrobial agent against multiple pathogenic microbes
  137. Photocatalytic treatment of organic dyes using metal oxides and nanocomposites: A quantitative study
  138. Antifungal, antioxidant, and photocatalytic activities of greenly synthesized iron oxide nanoparticles
  139. Special Issue on Phytochemical and Pharmacological Scrutinization of Medicinal Plants
  140. Hepatoprotective effects of safranal on acetaminophen-induced hepatotoxicity in rats
  141. Chemical composition and biological properties of Thymus capitatus plants from Algerian high plains: A comparative and analytical study
  142. Chemical composition and bioactivities of the methanol root extracts of Saussurea costus
  143. In vivo protective effects of vitamin C against cyto-genotoxicity induced by Dysphania ambrosioides aqueous extract
  144. 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
  145. A comprehensive review uncovering the anticancerous potential of genkwanin (plant-derived compound) in several human carcinomas
  146. A study to investigate the anticancer potential of carvacrol via targeting Notch signaling in breast cancer
  147. Assessment of anti-diabetic properties of Ziziphus oenopolia (L.) wild edible fruit extract: In vitro and in silico investigations through molecular docking analysis
  148. Optimization of polyphenol extraction, phenolic profile by LC-ESI-MS/MS, antioxidant, anti-enzymatic, and cytotoxic activities of Physalis acutifolia
  149. Phytochemical screening, antioxidant properties, and photo-protective activities of Salvia balansae de Noé ex Coss
  150. Antihyperglycemic, antiglycation, anti-hypercholesteremic, and toxicity evaluation with gas chromatography mass spectrometry profiling for Aloe armatissima leaves
  151. Phyto-fabrication and characterization of gold nanoparticles by using Timur (Zanthoxylum armatum DC) and their effect on wound healing
  152. Does Erodium trifolium (Cav.) Guitt exhibit medicinal properties? Response elements from phytochemical profiling, enzyme-inhibiting, and antioxidant and antimicrobial activities
  153. 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
  154. 6-Methoxyflavone improves anxiety, depression, and memory by increasing monoamines in mice brain: HPLC analysis and in silico studies
  155. Simultaneous extraction and quantification of hydrophilic and lipophilic antioxidants in Solanum lycopersicum L. varieties marketed in Saudi Arabia
  156. Biological evaluation of CH3OH and C2H5OH of Berberis vulgaris for in vivo antileishmanial potential against Leishmania tropica in murine models
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