Construction of a HIV-1 subtype C 3D model using homology modeling and in-silico docking, molecular dynamics simulation, and MM-GBSA calculation of second-generation HIV-1 maturation inhibitor(s)

Maturation inhibitors (MIs) efficiently block HIV-1 maturation by inhibiting the cleavage of the capsid protein and spacer peptide 1 (CA-SP1) leading to the production of immature and non-infectious virus particles. We have previously reported that second-generation MIs were more potent than bevirimat (BVM) against HIV-1 subtype C. In-silico studies on interaction of with BVM and their analogs have been limited to HIV-1 subtype B(5I4T) due to lack of an available 3D structure for HIV-1 subtype C virus. In our current study, we have developed a 3D model of HIV-1C Gag CA-SP1 region using protein homology modeling with HIV-1 subtype B(514T) as a template. The HIV-1 C homology model generated was extensively validated using several online tools and served as a template to perform molecular docking studies with eight well-characterized MIs. The docked complex of HIV-1C and all nine MIs was subjected to molecular dynamics simulation for 100 ns using AMBER and binding free energy calculations were done using MM-GBSA. Based on our data, CV8611 exhibited highest binding energy of −6.5 Kcal/mol among all BVM analogs. CV8611 formed strong interactions with Gly222 and Met235 of HIV-1C Gag CA-SP1 during MD simulation and remained intact. The root mean square deviation and root mean square fluctuation values of the complex were stable during the simulations. Our study is the first to report construction and validation of 3D model for the HIV-1C Gag CA-SP1, which could serve as a crucial tool in the structure-aided design of novel and broadly acting maturation inhibitors. Communicated by Ramaswamy H. Sarma