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

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