Theoretical exploration of the binding selectivity of inhibitors to BRD7 and BRD9 with multiple short molecular dynamics simulations.

Bromodomain-containing proteins 7 and 9 (BRD7 and BRD9) have been considered as potential targets of clinical drug design toward treatment of human cancers and other diseases. Multiple short molecular dynamics simulations and binding free energy predictions were carried out to decipher the binding selectivity of three inhibitors 4L2, 5U6, and 6KT toward BRD7 and BRD9. The results show that 4L2 has more favorable binding ability to BRD7 over BRD9 compared to 5U6 and 6KT, while 5U6 and 6KT possess more favorable associations with BRD9 than BRD7.

Binding selectivity of inhibitors toward the first over the second bromodomain of BRD4: theoretical insights from free energy calculations and multiple short molecular dynamics simulations.

Bromodomain-containing protein 4 (BRD4) plays an important role in mediating gene transcription involved in cancers and non-cancer diseases such as acute heart failure and inflammatory diseases. In this work, multiple short molecular dynamics (MSMD) simulations are integrated with a molecular mechanics generalized Born surface area (MM-GBSA) approach to decipher binding selectivity of three inhibitors 8NS, 82Y, and 837 toward two domains BD1 and BD2 of BRD4. The results demonstrate that the enthalpy effects play critical roles in selectivity identification of inhibitors toward BD1 and BD2, determining that 8NS has better selectivity toward BD2 than BD1, while 82Y and 837 more favorably bind to BD1 than BD2.