title: Combining pharmacophore, docking and substructure search approaches to identify and optimize novel B-RafV600E inhibitors.
abstract: In this study for searching novel B-Raf(V600E) inhibitors, pharmacophore-based virtual screening identified 1 as a hit bearing 5-benzylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-dione. Based on 1, scaffold hopping inspired by molecular docking discovered 5-(furan-2-ylmethylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione as a new and better scaffold. Substructure search with the new scaffold identified 28 active compounds, among which 12 compounds (42.9%) showed IC(50) less than 1 μM. Especially, compound 3o, which is 10-fold more potent than the hit 1, is a potent inhibitor comparable to that of the marketed drug vemurafenib.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Xu
authors.forename: Guirui
authors.initials: G
authors.lastname: Yan
authors.forename: Gaihong
authors.initials: G
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhu
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Heyao
authors.initials: H
authors.lastname: Wang
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
mesh_terms: D019943:Amino Acid Substitution; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D020125:Mutation, Missense; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D048493:Proto-Oncogene Proteins B-raf