Pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation and biological evaluation for the discovery of novel BRD4 inhibitors

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 by using pharmacophore based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules out of twelve hits were found to be active in bioactivity tests. Among the molecules, compound 5 exhibited potent anticancer activity, the IC₅₀ values against human cancer cell lines MV4-11, A375 and HeLa were 4.2 μM, 7.1 μM 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 compound 5.

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In this study, pharmacophore based virtual screening, molecular docking, and molecular dynamics simulation were employed to get novel BRD4 inhibitors. 12 hit were obtained for bioactivity test and 2 of them showed good anticancer activity. Among them, compound 5 exhibited potent anticancer activity against 3 cancer cell lines. Colony formation assay, cell cycle and apoptosis analysis, wound-healing migration assay were carried out of learn the bioactivity of compound 5. The result suggested a promising candidate for further optimization.

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