Design and evaluation of novel selective BET BD2 inhibitors by combining QSAR, molecular docking and molecular dynamics simulation techniques

Bromodomain and extra terminal domain (BET) proteins play important roles in biological processes such as cell proliferation, differentiation, and signaling, and are involved in the occurrence and development of many diseases, including cancer and inflammatory diseases. Selective inhibitors targeting the first bromodomain (BD1) or the second bromodomain (BD2) have triggered a new wave of research to produce more specific and safer drugs. In this study, 37 novel selective BET BD2 inhibitors with anti‐inflammatory activity are selected to construct robust Topomer CoMFA (q2=0.689, r2=0.916) and HQSAR (q2=0.805, r2=0.906) models, and both models have good external prediction ability. Based on QSAR results and ZINC15 database screening, 23 new compounds with ideal inhibitory activity are successfully designed. The stability and feasibility of binding the newly designed compounds to the target protein are further verified by molecular docking and molecular dynamics simulation validation. In conclusion, this work not only provides a reliable QSAR model as a screening tool for future anti‐inflammatory drug development, but also provides a theoretical basis for the design and modification of subsequent selective BET BD2 inhibitors.