title: In silico investigation of potential TRAF6 inhibitor from traditional Chinese medicine against cancers.
abstract: It has been indicated that tumor necrosis factor receptor-associated factor-6 (TRAF6) will upregulate the expression of hypoxia-inducible factor-1α (HIF-1α) and promote tumor angiogenesis. TRAF6 proteins can be treated as drug target proteins for a differentiation therapy against cancers. As structural disordered disposition in the protein may induce the side-effect and reduce the occupancy for ligand to bind with target protein, PONDR-Fit protocol was performed to predict the disordered disposition in TRAF6 protein before virtual screening. TCM compounds from the TCM Database@Taiwan were employed for virtual screening to identify potent compounds as lead compounds of TRAF6 inhibitor. After virtual screening, the MD simulation was performed to validate the stability of interactions between TRAF6 proteins and each ligand. The top TCM compounds, tryptophan, diiodotyrosine, and saussureamine C, extracted from Saussurea lappa Clarke, Bos taurus domesticus Gmelin, and Lycium chinense Mill., have higher binding affinities with target protein in docking simulation. However, the docking pose of TRAF6 protein with tryptophan is not stable under dynamic condition. For the other two TCM candidates, diiodotyrosine and saussureamine C maintain the similar docking poses under dynamic conditions. Hence, we propose the TCM compounds, diiodotyrosine and saussureamine C, as potential candidates as lead compounds for further study in drug development process with the TRAF6 protein against cancer.
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 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 ; Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung 40402, Taiwan ; Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan.
authors.forename: Calvin Yu-Chian
authors.identifier: 0000-0003-3306-250X
authors.initials: CY
authors.lastname: Chen
mesh_terms: D000818:Animals; D001216:Asparagine / Q000031:analogs & derivatives / Q000737:chemistry; D002417:Cattle; D018360:Crystallography, X-Ray; D004105:Diiodotyrosine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008024:Ligands; D008516:Medicine, Chinese Traditional / Q000379:methods*; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic; D011485:Protein Binding; D017433:Protein Structure, Secondary; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors*; D014364:Tryptophan / Q000737:chemistry
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D048029:TNF Receptor-Associated Factor 6; C000595384:saussureamine C; D004105:Diiodotyrosine; D001216:Asparagine; D014364:Tryptophan
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