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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. Furthermore, estimations of residue-based free energy decompositions further identify that four common residue pairs, including (F155, F44), (V160, V49), (Y168, Y57) and (Y217, Y106) in (BRD7, BRD9) generate obvious binding differences with 4L2, 5U6, and 6KT, which mostly drives the binding selectivity of 4L2, 5U6, and 6KT to BRD7 and BRD9. Dynamic information arising from trajectory analysis also suggests that inhibitor bindings affect structural flexibility and motion modes, which is responsible for the partial selectivity of 4L2, 5U6, and 6KT toward BRD7 and BRD9. As per our expectation, this study theoretically provides useful hints for design of dual inhibitors with high selectivity on BRD7 and BRD9.

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