Insight Into Selective Binding Mechanism of BRD4 to Inhibitors 21r, Lpd22, and XY221 Through Molecular Docking and MD Simulations

ABSTRACT Two bromodomains BRD4‐BD1 and BRD4‐BD2 of BRD4 play a critical role in the design of inhibitors targeting various diseases such as inflammatory diseases and cancers. In the present study, multiple computational methods, including molecular docking, multiple replica MD simulations, and binding free energy calculations, were utilized to study the selective binding of three novel inhibitors, 21r, Lpd22, and XY221, to the two bromodomains BRD4‐BD1 and BRD4‐BD2, respectively. When these three inhibitors interact with BRD4‐BD1 and BRD4‐BD2, they exert distinct effects on their internal dynamics, leading to changes in their interaction patterns with critical residues of BRD4. Residues Trp81/Trp374, Pro82/Pro375, Val87/Val380, Leu92/Leu385, Leu94/Leu387, Asn140/Asn433, and Ile146/Val439 in BRD4‐BD1 and BRD4‐BD2 play a critical role in the selectivity binding to these three inhibitors. Meanwhile, electrostatic interactions and nonpolar interactions are the main driving factors influencing their interactions. This provides theoretical guidance for the rational design of selective inhibitors targeting these two bromodomains of BRD4.