Docking and 3D-QSAR studies of BMS-806 analogs as HIV-1 gp120 entry inhibitors

BMS-378806 (BMS-806) is a small molecule that blocks the binding of host-cell CD4 with viral gp120 protein and therefore inhibits the first steps of HIV-1 infection. Recently, 36 analogs compounds of BMS-806 were synthesized and their biological activity evaluated. Based on these compounds, a molecular docking was firstly performed with BMS-806 to the gp120 cavity in order to get a representative ligand conformation for the 3D-QSAR process. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were then conducted for these 36 compounds. CoMFA and CoMSIA models give reliable correlative and predictive abilities but the CoMFA model performance was slightly better than CoMSIA. CoMFA contours were analysed and have been correlated to the gp120 viral protein. The discussion indicates several key fragment positions on the ligands and their implications on the gp120 protein binding. The computational approach used in this paper provides reliable clues for further design of small molecules gp120/CD4 inhibitors based on the BMS-806.