title: In silico investigation of potential mTOR inhibitors from traditional Chinese medicine for treatment of Leigh syndrome.
abstract: A recent research demonstrates that the inhibition of mammalian target of rapamycin (mTOR) improves survival and health for patients with Leigh syndrome. mTOR proteins can be treated as drug target proteins against Leigh syndrome and other mitochondrial disorders. In this study, we aim to identify potent TCM compounds from the TCM Database@Taiwan as lead compounds of mTOR inhibitors. PONDR-Fit protocol was employed to predict the disordered disposition in mTOR protein before virtual screening. After virtual screening, the MD simulation was employed to validate the stability of interactions between each ligand and mTOR protein in the docking poses from docking simulation. The top TCM compounds, picrasidine M and acerosin, have higher binding affinities with target protein in docking simulation than control. There have H-bonds with residues Val2240 and π interactions with common residue Trp2239. After MD simulation, the top TCM compounds maintain similar docking poses under dynamic conditions. The top two TCM compounds, picrasidine M and acerosin, were extracted from Picrasma quassioides (D. Don) Benn. and Vitex negundo L. Hence, we propose the TCM compounds, picrasidine M and acerosin, as potential candidates as lead compounds for further study in drug development process with the mTOR protein against Leigh syndrome and other mitochondrial disorders.
authors.affiliation: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors.forename: Kuan-Chung
authors.initials: KC
authors.lastname: Chen
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan ; Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan ; Department of Neurosurgery, China Medical University Hospital, Taichung 40447, Taiwan.
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Lee
authors.affiliation: Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chen
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan ; Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan ; Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan ; Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung 40402, Taiwan.
authors.forename: Calvin Yu-Chian
authors.initials: CY
authors.lastname: Chen
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D055808:Drug Discovery; D006801:Humans; D007888:Leigh Disease / Q000188:drug therapy* / Q000473:pathology; D008516:Medicine, Chinese Traditional; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D021281:Quantitative Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013624:Taiwan
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases