title: Identification of novel BRAF kinase inhibitors with structure-based virtual screening.
abstract: VRAF murine sarcoma viral oncogene homologue B1 (BRAF) kinase has proved to be a promising target for the development of therapeutics for the treatment of a variety of human cancers. Here, we report the first example of a successful application of the structure-based virtual screening to identify novel BRAF inhibitors. These inhibitors have desirable physicochemical properties as a drug candidate, and compound 1 revealed a submicromolar binding affinity (0.7 μM). Therefore, they may serve as promising lead compounds for further development by structure-activity relationship (SAR) studies to optimize the inhibitory activities. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of BRAF are discussed in detail.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Republic of Korea. hspark@sejong.ac.kr
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.forename: Hwanho
authors.initials: H
authors.lastname: Choi
authors.forename: Seunghee
authors.initials: S
authors.lastname: Hong
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011485:Protein Binding; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; C508204:SB-590885; D000255:Adenosine Triphosphate; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf