3D-QSAR and docking studies of HIV-1 protease inhibitors using R-group search and Surflex-dock

In this paper, a three-dimensional quantitative structure–activity relationships study for 38 HIV-1 protease inhibitors was established using Topomer CoMFA. The multiple correlation coefficients of fitting, cross-validation, and external validation were 0.959, 0.867, and 0.964, respectively. The results indicated that the model obtained has both favorable estimation stability and good prediction capability. Topomer Search was used to search R-group from ZINC database. As the result, a series of R-groups with relatively high activity contribution was obtained. By No. 32 molecule filtering, 10 Ra and 6 Rb groups were selected. We employed the 10 Ra and 6 Rb groups to alternately substitutes for the Ra and Rb of sample 32. Finally, we designed 60 new compounds with higher activity than that of the template molecule. The results suggested the Topomer Search technology could be effectively used to screen and design new HIV-1 protease inhibitors and has good predictive capability to guide the design of new HIV/AIDS drugs. As the ligands, the training molecules and new designed compounds were used for molecular docking to study the interaction mode with the protein receptor. As the results, we found that the ligands would form the hydrogen-bonding interactions with Asp25, Asp29, Asp30, Gly48, and Ile50 of the protein receptor generally.