Molecular mechanism study of several inhibitors binding to BRD9 bromodomain based on molecular simulations.

Bromodomain-containing protein 9 (BRD9) has been employed as a potential target for anticancer drugs in recent years. In this work, molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and per residue energy decomposition approaches were performed to elucidate the different binding modes between four pyridinone-like scaffold inhibitors and BRD9 bromodomain. Analysis results indicate that non-polar contribution mainly deriving from van der Waals energy is a critical impact on binding affinity of inhibitors against BRD9. Some key residues Phe44, Phe47, Val49, and Ile53 (at ZA loop) enhance the binding energy of inhibitors in BRD9 by means of providing hydrophobic interactions. Moreover, it is observed that BRD9 is anchored by the formation of a stable hydrogen bond between the carbonyl of the inhibitors and the residue Asn100 (at BC loop), and a strong π-π stacking interaction formed between the residue Tyr106 (at BC loop) and the inhibitors. The existence of dimethoxyphenyl structure and the aromatic ring merged to pyridinone scaffold are useful to enhance the BRD9 binding affinity. These findings should guide the rational design of more prospective inhibitors targeting BRD9. Communicated by Ramaswamy H. Sarma.