Abstract:
The HIV-1 accessory proteins (Vpr, Vif, Vpu, and Nef) are multifunctional proteins that play a critical role in the virus progression and contributing to AIDS pathogenesis. These proteins engage with numerous host cellular proteins to execute various functions, promoting viral replication. These proteins show remarkable conformational plasticity i.e. they frequently undergo substantial structural changes upon binding to their targets. In this research, conformational dynamics of these proteins are thoroughly investigated thorough integrated computational modelling and molecular dynamics (MD) simulation techniques in order to explain functional mechanisms and most importantly to explore druggability against these proteins. Conformational analysis revealed novel insights into Vpr's conformational space, particularly the stable embedding of the Vpr C-terminal helix (residues 54-77) within lipid bilayers, marking its likely role as the transmembrane core of the ion channel structure. Full length Vpr undergoes large structural deviations inside lipid bilayer resulting in novel conformations of Vpr. The proposed multimeric Vpr ion channel models in this research offered the first rational attempt for structural understanding of this oligomeric complex which could enhance the therapeutic options. On the other hand, Viprinin and its two potent derivatives emerged as effective inhibitors for Vpr. These findings provide pivotal insights into structure-based drug discovery efforts against HIV-1 accessory proteins. The proposed ion channel models and inhibitor compounds establish a computational framework for future investigations into HIV-1 Vpr structural biology and drug development. Additionally, the analysis of Nef's conformational space identified a conserved druggable pocket implicated in homodimerization, presenting a potential therapeutic target. Utilizing fragment-based approaches, novel lead compounds against Nef were generated and further optimized through advanced MD simulations. These compounds could serve as the starting point for initial stage clinical trials for the discovery of new antiretroviral compounds targeting Nef. This research will lead to development of novel therapeutic options to combat HIV-1 infection in forseeable future in turn leading to significant decrease in loss of lives due to AIDS.
