Binding Selectivity of Inhibitors to BRD2 Uncovered by Molecular Docking and Molecular Dynamics Simulations

Abstract

Bromodomain-containing protein 2 (BRD2) plays a significant role in the development and progression of various diseases. Investigating the binding selectivity of the two bromodomains BD1 and BD2 of BRD2 (BRD2-BD1 and BRD2-BD2) with specific inhibitors can provide valuable insights for rational design of novel therapeutic drugs. Thus, molecular dynamics (MD) simulations are employed to evaluate the selective mechanisms of three BRD2 inhibitors, Spd16, BBC0403, and SJ1461, toward BRD2-BD1 and BRD2-BD2. Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) and Solvation Interaction Energy (SIE) methods are further employed to analyze the interaction modes and compare the binding free energies of BRD2-BD1 and BRD2-BD2 with these inhibitors. Although these inhibitors exert different effects on the internal structures of BRD2-BD1 and BRD2-BD2, their interaction patterns with these two bromodomains are similar. Phe372, Leu381, Tyr386, and Cys425 play key roles in the interaction between BRD2-BD2 and these three inhibitors, while Pro98, Leu108, Asn156, and Ile162 are the critical residues for the binding of BRD2-BD1 with these inhibitors. Non-polar interactions, particularly van der Waals interactions, serve as the primary driving force behind the binding of these inhibitors with BRD2-BD1 and BRD2-BD2. The findings of this study provide valuable insights for the rational design of novel BRD2 inhibitors.