Study on the Binding Selectivity of Three Pyridinone Analogs With BRD4 Using Multiple Molecular Dynamics Simulations

Bromodomain‐containing protein 4 (BRD4) regulates transcription via its two homologous bromodomains, BRD4‐BD2 and BRD4‐BD1. The selective interaction mechanisms of three pyridinone inhibitors, Spd17, Spd21, and Spd33, with BRD4‐BD2 and BRD4‐BD1, were explored using multiple MD simulations, MM‐GBSA, and SIE. The energy results indicate that these pyridinone inhibitors show greater selectivity for BRD4‐BD1 compared to BRD4‐BD2, while non‐polar interactions, especially van der Waals interactions like CH‐π and π – π interactions are the key factors for interacting with BRD4‐BD1 and BRD4‐BD2. The energy differences of residues Val87/Val380, Leu92/Leu385, Asn140/Asn433, and Ile146/Val439 in BRD4‐BD1 and BRD4‐BD2 make contributions to their selectivity. The findings provide certain insights for the development of new BRD4 inhibitors.