IN SILICO DISCOVERY OF NEW INHIBITORS TARGETING HIV-1 REVERSE TRANSCRIPTASE: EXPLORING NOVEL APPROACHES FOR ANTIRETROVIRAL THERAPY

Abstract

Zidovudine, an FDA approved drug used in the treatment of Acquired Immunodeficiency Syndrome caused due to Human Immunodeficiency Virus . It acts as an inhibitor of HIV-1 nucleoside reverse transcriptase enzyme which is essential for the replication of viral genome and prevent in spreading of this disease. As a result it protect further transmission of disease and prevent further damage to the immunity of the infected person. It is a landmark antiretroviral agent approved by the U.S. Food and Drug Administration (FDA), remains a critical therapeutic tool in managing Acquired Immunodeficiency Syndrome (AIDS) caused by the Human Immunodeficiency Virus (HIV). Functioning as a competitive inhibitor of the HIV-1 nucleoside reverse transcriptase (RT) enzyme, zidovudine disrupts the viral replication cycle by impeding the conversion of viral RNA into proviral DNA. This enzymatic interference prevents the integration of viral genetic material into host cells, thereby curbing the spread of infection and mitigating progressive immune system deterioration. By reducing viral load, the drug not only delays disease progression but also lowers the risk of secondary infections and transmission, offering a dual therapeutic and prophylactic benefit. Structurally, zidovudine is a synthetic thymidine analogue, a feature that enables its incorporation into nascent viral DNA strands during replication. Unlike endogenous thymidine, however, its modified 3'-azido group induces premature chain termination, halting DNA synthesis. This mechanism underscores the drug’s specificity for the viral reverse transcriptase enzyme, which exhibits a higher affinity for zidovudine than human DNA polymerases. Despite its efficacy, long-term use of zidovudine is limited by challenges such as mitochondrial toxicity (due to inhibition of mitochondrial γ-DNA polymerase) and the emergence of drug-resistant HIV strains. These limitations highlight the urgent need for novel nucleoside reverse transcriptase inhibitors (NRTIs) with improved safety profiles and resistance barriers. P a g e | 7 In this research, zidovudine has been employed as a reference ligand to identify structurally analogous compounds with potential antiretroviral activity. Leveraging computational tools, scientists have screened libraries of molecules based on similarity scores derived from zidovudine’s pharmacophoric features— particularly its sugar moiety, azido group, and aromatic base. Molecular docking simulations further evaluate these candidates by predicting their binding affinities and interaction patterns with the HIV-1 RT active site. For instance, analogues with substitutions at the 3' position or modifications to the sugar backbone have shown enhanced binding stability in silico, suggesting improved inhibitory potency. Notably, several candidates identified through these virtual screenings are already undergoing clinical trials for HIV and other viral diseases, demonstrating the translational potential of structure-based drug design. The integration of computational modeling into this research streamlines the drug discovery process by prioritizing high-affinity candidates for experimental validation. Studies comparing binding energies, hydrogen-bond interactions, and hydrophobic contacts between zidovudine and its analogues provide mechanistic insights into RT inhibition.