title: Potential smoothened inhibitor from traditional Chinese medicine against the disease of diabetes, obesity, and cancer.
abstract: Nowadays, obesity becomes a serious global problem, which can induce a series of diseases such as type 2 diabetes mellitus, cancer, cardiovascular disease, metabolic syndrome, and stoke. For the mechanisms of diseases, the hedgehog signaling pathway plays an important role in body patterning during embryogenesis. For this reason, smoothened homologue (Smo) protein had been indicated as the drug target. In addition, the small-molecule Smo inhibitor had also been used in oncology clinical trials. To improve drug development of TCM compounds, we aim to investigate the potent lead compounds as Smo inhibitor from the TCM compounds in TCM Database@Taiwan. The top three TCM compounds, precatorine, labiatic acid, and 2,2'-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), have displayed higher potent binding affinities than the positive control, LY2940680, in the docking simulation. After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and Smo protein under dynamic conditions, top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain. Hence, we propose precatorine, labiatic acid, and 2,2'-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) as potential lead compounds for further study in drug development process with the Smo protein.
authors.affiliation: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors.forename: Kuan-Chung
authors.identifier: 0000-0003-0223-1577
authors.initials: KC
authors.lastname: Chen
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan ; Department of Acupuncture, China Medical University Hospital, Taichung, Taiwan ; Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung, Taiwan.
authors.forename: Mao-Feng
authors.identifier: 0000-0003-1465-0330
authors.initials: MF
authors.lastname: Sun
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.
authors.forename: Cheng-Chun
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung, Taiwan ; Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan ; School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan ; Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Calvin Yu-Chian
authors.identifier: 0000-0003-3306-250X
authors.initials: CY
authors.lastname: Chen
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008516:Medicine, Chinese Traditional; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000188:drug therapy* / Q000473:pathology; D010793:Phthalazines / Q000737:chemistry; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000072086:Smoothened Receptor; D013624:Taiwan
chemical_list: C581399:LY2940680; D010793:Phthalazines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor