10 Identification of novel inhibitors of P13K/AKT pathways: an integrated in-silico study towards the development of a new therapeutic agent against ovarian cancer
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Misbaudeen Abdul-Hammed
Abstract
Ovarian cancer is a crucial gynaecological unmet medical disease with a high mortality rate. According to recent research, the phosphoinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways are hyper-activated in the majority of ovarian cancer patients, necessitating the use of inhibitors. Over the years, phytochemicals have been used as alternative sources of therapeutic agents due to their reported biological activities and limited side effects. Curcuma longa (Tumeric), a reported ayurvedic medicine has also been noted for its anti-cancer properties. Thus, 155 phytochemicals from this plant and 2 reference drugs were evaluated for their inhibitory prowess against P13K/AKT receptor using a computer-aided drug design approach. The binding scores and inhibiting efficiencies were obtained via virtual screening. Molinspiration Chemoinformatics and SwissADME tools were used to investigate the drug-likeness properties and oral bioavailability of the compounds selected, while the ADMET SAR-2 website was used to conduct the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis. Other analyses performed on the selected compounds include bioactivity, activity spectra for substances (PASS) prediction, binding mode, and molecular interaction. The results revealed that Hopenone 1 (−8.8 kcal mol−1) and Epriprocurcumenol (−7.8 kcal mol−1) are potent inhibitors of the P13K receptor, while Epiprocurcumenol (−9.0 kcal mol−1), Procurcuminol (−8.6 kcal mol−1) and Curlone (−8.3 kcal mol−1) are potential inhibitors of AKT receptor. In comparison to Topotecan and Melphalan, they have better binding affinities, oral bioavailability, drug-likeness characteristics, ADMET properties, bioactivities, PASS properties, binding mechanism, and also interact well with the active site of the target receptor. As a result, this preliminary investigation suggests that these chemicals should be studied further for the design of novel ovarian cancer therapeutics.
Abstract
Ovarian cancer is a crucial gynaecological unmet medical disease with a high mortality rate. According to recent research, the phosphoinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways are hyper-activated in the majority of ovarian cancer patients, necessitating the use of inhibitors. Over the years, phytochemicals have been used as alternative sources of therapeutic agents due to their reported biological activities and limited side effects. Curcuma longa (Tumeric), a reported ayurvedic medicine has also been noted for its anti-cancer properties. Thus, 155 phytochemicals from this plant and 2 reference drugs were evaluated for their inhibitory prowess against P13K/AKT receptor using a computer-aided drug design approach. The binding scores and inhibiting efficiencies were obtained via virtual screening. Molinspiration Chemoinformatics and SwissADME tools were used to investigate the drug-likeness properties and oral bioavailability of the compounds selected, while the ADMET SAR-2 website was used to conduct the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis. Other analyses performed on the selected compounds include bioactivity, activity spectra for substances (PASS) prediction, binding mode, and molecular interaction. The results revealed that Hopenone 1 (−8.8 kcal mol−1) and Epriprocurcumenol (−7.8 kcal mol−1) are potent inhibitors of the P13K receptor, while Epiprocurcumenol (−9.0 kcal mol−1), Procurcuminol (−8.6 kcal mol−1) and Curlone (−8.3 kcal mol−1) are potential inhibitors of AKT receptor. In comparison to Topotecan and Melphalan, they have better binding affinities, oral bioavailability, drug-likeness characteristics, ADMET properties, bioactivities, PASS properties, binding mechanism, and also interact well with the active site of the target receptor. As a result, this preliminary investigation suggests that these chemicals should be studied further for the design of novel ovarian cancer therapeutics.
Kapitel in diesem Buch
- Frontmatter I
- Preface of the Book of Proceedings of the Virtual Conference on Chemistry and its Applications (VCCA-2022). V
- Contents VII
- List of contributing authors XIX
- 1 Dipeptidyl peptidase IV: a multifunctional enzyme with implications in several pathologies including cancer 1
- 2 A mini review on the prospects of Fagara zanthoxyloides extract based composites: a remedy for COVID-19 and associated replica? 57
- 3 Triterpenoids of antibacterial extracts from the leaves of Bersama abyssinica Fresen (Francoaceae) 75
- 4 Physicochemical assessment and insilico studies on the interaction of 5-HT2c receptor with herbal medication bioactive compounds used in the treatment of premature ejaculation 87
- 5 Xanthoangelol, geranilated chalcone compound, isolation from pudau leaves (Artocarpus kemando Miq.) as antibacterial and anticancer 121
- 6 Exploration of bioactive compounds from Mangifera indica (Mango) as probable inhibitors of thymidylate synthase and nuclear factor kappa-B (NF-Κb) in colorectal cancer management 137
- 7 Identification of potential inhibitors of thymidylate synthase (TS) (PDB ID: 6QXH) and nuclear factor kappa-B (NF–κB) (PDB ID: 1A3Q) from Capsicum annuum (bell pepper) towards the development of new therapeutic drugs against colorectal cancer (CRC) 165
- 8 Synthesis, characterization and in vitro activity study of some organotin(IV) carboxylates against leukemia cancer cell, L-1210 199
- 9 Phytochemicals from Annona muricata (Sour Sop) as potential inhibitors of SARS-CoV-2 main protease (Mpro) and spike receptor protein: a structure-based drug design studies and chemoinformatics analyses 207
- 10 Identification of novel inhibitors of P13K/AKT pathways: an integrated in-silico study towards the development of a new therapeutic agent against ovarian cancer 231
- 11 Immobilization of α-amylase from Aspergillus fumigatus using adsorption method onto zeolite 261
- 12 Phytochemical components and GC–MS analysis of Petiveria alliaceae L. fractions and volatile oils 273
- 13 Characterization of crude saponins from stem bark extract of Parinari curatellifolia and evaluation of its antioxidant and antibacterial activities 287
- 14 Physicochemical and free radical scavenging activity of Adansonia digitata seed oil 307
- 15 Photoprotection strategies with antioxidant extracts: a new vision 321
- 16 A systematic DFT study of arsenic doped iron cluster AsFen (n = 1–4) 335
- 17 Effect of case-based learning, team-based learning and regular teaching methods on secondary school students’ self-concept in chemistry in Maara sub-county, Tharaka Nithi county, Kenya 345
- 18 Random and block architectures of N-arylitaconimide monomers with methyl methacrylate 359
- 19 Evaluation of phytochemicals and amino acid profiles of four vegetables grown on a glyphosate contaminated soil in Southwestern Nigeria 399
- Index 411
Kapitel in diesem Buch
- Frontmatter I
- Preface of the Book of Proceedings of the Virtual Conference on Chemistry and its Applications (VCCA-2022). V
- Contents VII
- List of contributing authors XIX
- 1 Dipeptidyl peptidase IV: a multifunctional enzyme with implications in several pathologies including cancer 1
- 2 A mini review on the prospects of Fagara zanthoxyloides extract based composites: a remedy for COVID-19 and associated replica? 57
- 3 Triterpenoids of antibacterial extracts from the leaves of Bersama abyssinica Fresen (Francoaceae) 75
- 4 Physicochemical assessment and insilico studies on the interaction of 5-HT2c receptor with herbal medication bioactive compounds used in the treatment of premature ejaculation 87
- 5 Xanthoangelol, geranilated chalcone compound, isolation from pudau leaves (Artocarpus kemando Miq.) as antibacterial and anticancer 121
- 6 Exploration of bioactive compounds from Mangifera indica (Mango) as probable inhibitors of thymidylate synthase and nuclear factor kappa-B (NF-Κb) in colorectal cancer management 137
- 7 Identification of potential inhibitors of thymidylate synthase (TS) (PDB ID: 6QXH) and nuclear factor kappa-B (NF–κB) (PDB ID: 1A3Q) from Capsicum annuum (bell pepper) towards the development of new therapeutic drugs against colorectal cancer (CRC) 165
- 8 Synthesis, characterization and in vitro activity study of some organotin(IV) carboxylates against leukemia cancer cell, L-1210 199
- 9 Phytochemicals from Annona muricata (Sour Sop) as potential inhibitors of SARS-CoV-2 main protease (Mpro) and spike receptor protein: a structure-based drug design studies and chemoinformatics analyses 207
- 10 Identification of novel inhibitors of P13K/AKT pathways: an integrated in-silico study towards the development of a new therapeutic agent against ovarian cancer 231
- 11 Immobilization of α-amylase from Aspergillus fumigatus using adsorption method onto zeolite 261
- 12 Phytochemical components and GC–MS analysis of Petiveria alliaceae L. fractions and volatile oils 273
- 13 Characterization of crude saponins from stem bark extract of Parinari curatellifolia and evaluation of its antioxidant and antibacterial activities 287
- 14 Physicochemical and free radical scavenging activity of Adansonia digitata seed oil 307
- 15 Photoprotection strategies with antioxidant extracts: a new vision 321
- 16 A systematic DFT study of arsenic doped iron cluster AsFen (n = 1–4) 335
- 17 Effect of case-based learning, team-based learning and regular teaching methods on secondary school students’ self-concept in chemistry in Maara sub-county, Tharaka Nithi county, Kenya 345
- 18 Random and block architectures of N-arylitaconimide monomers with methyl methacrylate 359
- 19 Evaluation of phytochemicals and amino acid profiles of four vegetables grown on a glyphosate contaminated soil in Southwestern Nigeria 399
- Index 411
