Pharmacophore‐based virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation for the discovery of novel BRD4 inhibitors. (9th October 2017)

• Record Type: Journal Article
• Authors: Yan, Guoyi; Hou, Manzhou; Luo, Jiang; Pu, Chunlan; Hou, Xueyan; Lan, Suke; Li, Rui
• Is Part Of: Chemical biology & drug design. Volume 91:Number 2(2018)
• Page Start: 478
• Page End: 490
• Publication Date: 2017-10-09
• Subjects: antiproliferation -- BRD4 -- drug discovery -- virtual screening; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13109
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study, an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors using pharmacophore‐based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules of twelve hits were found to be active in bioactivity tests. Among the molecules, compound5 exhibited potent anticancer activity, and the IC50 values against human cancer cell lines MV4‐11, A375, and HeLa were 4.2, 7.1, and 11.6 μm, respectively. After that, colony formation assay, cell cycle, apoptosis analysis, wound‐healing migration assay, and Western blotting were carried out to learn the bioactivity of compound5 . Abstract : In this study, pharmacophore‐based virtual screening, molecular docking, and molecular dynamics simulation were employed to get novel BRD4 inhibitors. Twelve hits were obtained for bioactivity test and two of them showed good anticancer activity. Among them, compound5 exhibited potent anticancer activity against three cancer cell lines. Colony formation assay, cell cycle and apoptosis analysis, and wound‐healing migration assay were carried out to learn the bioactivity of compound5 . The result suggested a promising candidate for further optimization.