Selective inhibition mechanism of three inhibitors to BRD4 uncovered by molecular docking and molecular dynamics simulations

• DOI: 10.1080/1062936x.2024.2447071
• Publication Date: 2025-01-08T09:56:11Z
• Authors: W. Chen; L. Sang; R. Wang; D. Zou; L. Chen
• Keywords: Docking (animal)

Bromodomain-containing protein 4 (BRD4) plays an important role in gene transcription a variety of diseases, including inflammation and cancer. However, the mechanism by which BRD4 inhibitors bind selectively to its bromodomain 1 (BRD4-BD1) 2 (BRD4-BD2) remains unclear. Studying interaction between will provide new ideas for drug development disease treatment. To explore molecular selective binding three novel phenoxypyridone Cpd11, Cpd14, Cpd23 BRD4-BD1 BRD4-BD2, respectively, docking, dynamics (MD) simulation, free energy calculation containing mechanics generalized born surface area (MM-GBSA) solvation (SIE) were achieved. The results show that these have different effects on internal but key interactions are similar. Key residues Ile146/Val439, Trp81/Trp374, Phe83/Phe375, Val87/Val380, Leu92/Leu385, Leu94/Leu387, Tyr97/Tyr390, Asn140/Asn433, play BRD4-BD2 inhibitors. At same time, non-polar interactions, especially van der Waals main drivers with BRD4-BD2. These useful dynamic information highly targeting