Identification of novel BRD4 inhibitors by pharmacophore screening, molecular docking, and molecular dynamics simulation

Bromodomain-containing protein 4 (BRD4), as an epigenetic reader, can regulate chromatin structure and gene expression via recognizing and binding acetylated lysine in histones. BRD4 promotes the expres-sion of tumor genes, such as c-Myc and Bcl-2, so it has been regarded as an attractive target for can-cers. In this work, a hierarchical virtual screening approach was applied to identify potential BRD4 in-hibitors from ZINC database. 3D-QSAR pharmacophore model was firstly constructed, validated and used for virtual screening. Molecular docking was then followed to evaluate the binding mode and interac-tions of screened compounds with BRD4. On this basis, the best three hits ZINC02126438, ZINC16645732, ZINC00856805 were selected for molecular dynamics simulation and binding free energy calculation. Among them, ZINC16645732 had a better binding free energy than the positive drug PF-1. Our results suggested that ZINC16645732 might be a potential BRD4 inhibitor that should undergo further experi-mental analysis and modification. (c) 2022 Elsevier B.V. All rights reserved.

Automated summary

BRD4 is an epigenetic reader that regulates chromatin structure and gene expression by binding acetylated lysine in histones. A virtual screening approach was used to identify potential BRD4 inhibitors from the ZINC database. Molecular docking and molecular dynamics simulation revealed that ZINC16645732 might be a potential BRD4 inhibitor with better binding free energy than the positive drug PF-1, suggesting the need for further experimental analysis and modification.