Computational study on the selective inhibition mechanism of MS402 to the first and second bromodomains of BRD4

摘要: As a member of the bromodomain and extraterminal domain (BET) family, BRD4 is considered as potential target for cancer treatment. However, because highly conservation its two homologous bromodomains (BD1/BD2), selective inhibition each remains challenge. MS402 domain-selective inhibitor BRD4-BD1 over BRD4-BD2 reported recently. Understanding selectivity mechanism would be very useful further design more potent BD1-selectivity inhibitors. Molecular dynamics simulation, adaptive biasing force multiple-walker were performed to study toward here. Results demonstrate binds with lower binding free energy than BRD4-BD2. Residues Gln85, Pro86, Asn140, Ile146 are crucial MS402's selectively BRD4-BD1. needs overcome barrier dissociate from BD1 BD2 pocket. These findings will helpful rational structural modification existing inhibitors increase their BD1-selectivity.