Computer aided design of inhibitor molecules against Vpr protein from different HIV-1 subtypes.

HIV-1 is a retrovirus that affects the human immune system and consequently leads to the development of AIDS. The high mutation rate in HIV-1 produces different subtypes which underscores the development of new therapeutics against it. This study aims to develop a novel small molecule that can be used as a potential inhibitor against the Vpr protein of all the subtypes of HIV-1. The druggable pockets of the Vpr protein of each subtype were identified and the conformational stability of these pockets was studied. The structure-based Drug Design method was used to design small molecules against the high-scoring pocket from each subtype individually using AutoGrow4 software. Molecules with strong binding affinity were selected from each subtype individually and binding affinity was checked for all the subtypes. Considering druggability and ADMET properties, we have identified two novel molecules that act as potential Vpr protein inhibitors. Both the molecules were shown to form stable complexes with the Vpr proteins of all the subtypes. The biological activity of both molecules was examined using DFT calculation. This study may provide some insight into developing of new therapies in HIV-1 treatment by interrupting protein-protein interaction. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00318-4.