title: An in silico protocol for identifying mTOR inhibitors from natural products.
abstract: The mammalian target of rapamycin (mTOR) is an anti-cancer target. In this study, we propose an in silico protocol for identifying mTOR inhibitors from the ZINC natural product database. First, a three-dimensional quantitative structure-activity relationship pharmacophore model was built based on known mTOR inhibitors. The model was validated with an external test set, Fischer's randomization method, a decoy set and pharmacophore mapping conformation testing. The results showed that the model can predict the mTOR inhibition activity of the tested compounds. Virtual screening was performed based on the best pharmacophore model, and the results were then filtered using a molecular docking approach. In addition, molecular mechanics/generalized born surface area analysis was used to refine the selected candidates. The top 20 natural products were selected as potential mTOR inhibitors, and their structural scaffolds could serve as building blocks in designing drug-like molecules for mTOR inhibition.
authors.affiliation: Research Center for Drug Discovery & Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gu
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
mesh_terms: D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D001688:Biological Products; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases