title: Insight into molecular dynamics simulation of BRAF(V600E) and potent novel inhibitors for malignant melanoma.
abstract: BRAF inhibitors have changed the standard therapeutic protocol for advanced or metastatic melanoma which harbored notorious BRAF(V600E) single mutation. However, drug resistance to BRAF inhibitors happens just like other cancer treatment. In this study, we constructed the ideal BRAF(V600E)-modeled structure through homology modeling and introduced the method of structure-based docking or virtual screening from the large compound database. Through certain methods of molecular dynamics simulation, we realized that BRAF(V600E) had quite prominent difference of molecular character or structural variation from the wild-type BRAF protein. It might confer the metamorphic character of advanced melanoma for the patients who harbored BRAF(V600E) mutation. By the methods of ligand-based quantitative structure-activity relationship and molecular dynamics simulation, we further recommend that aknadicine and 16beta-hydroxy-19s-vindolinine N-oxide from the traditional Chinese medicine are potent novel inhibitors for the management of malignant melanoma in the future.
authors.affiliation: Department of Biomedical Informatics, Asia University, Taichung, Taiwan.
authors.forename: Hsin-Chieh
authors.initials: HC
authors.lastname: Tang
authors.affiliation: Department of Biomedical Informatics, Asia University, Taichung, Taiwan ; Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan ; Research Center for Chinese Medicine and Acupuncture, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Yu-Chian
authors.initials: YC
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008545:Melanoma / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF inhibitor; docking; ligand-based; quantitative structure-activity relationship (QSAR); structure-based; virtual screening