The binding mechanism of NHWD-870 to bromodomain-containing protein 4 based on molecular dynamics simulations and free energy calculation
Mingsong Shi 1, Jun He 1, Tiantian Weng 1, Na Shi 1, Wenyan Qi 1, Yong Guo 1, Tao Chen 1, Lijuan Chen 1, Dingguo Xu 2 3
Bromodomain and additional-terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers with tandem bromodomains. Small-molecule inhibitors of BET proteins really are a promising treatment strategy against cancer. For instance, NHWD-870 can hinder BRD4 (BD1 BD2). Presently, structural data on NHWD-870 bound BRD4 remain missing. Herein, we investigate interactions between NHWD-870 and BRD4 (BD1 and BD2) via molecular docking, molecular dynamics simulation, and binding free energy calculations. NHWD-870 demonstrated an identical binding interest in BD1 and BD2 of BRD4. Binding free energy calculations for that R/S conformations of NHWD-870 claim that the chiral center of NHWD-870 may confer similar roles upon the R and S conformations for binding with BRD4, facilitating the identification of novel BRD4 inhibitors.