Could AVG Derivatives Be Potential Antivirals Against HIV‐1? In‐Silico Targeting of Reverse Transcriptase

ABSTRACT Despite advances in antiretroviral therapy, the emergence of drug‐resistant HIV strains continues to challenge treatment efficacy. This study investigates the repurposing potential of AVG derivatives, originally designed as RSV inhibitors, against HIV‐1 reverse transcriptase (RT). Utilizing molecular docking and molecular dynamics simulations, nine AVG compounds were evaluated for their binding affinities to both the catalytic site and the allosteric Non‐Nucleoside Reverse Transcriptase Inhibitor (NNRTI)‐binding pocket of HIV‐1 RT. Results of this study revealed that among the nine derivatives compared, AVG‐436 and AVG‐388 showed significantly stronger affinity for the active site than NNRTIs such as tenofovir and abacavir. Conversely, AVG‐435 and AVG‐445 exhibited superior binding to the allosteric site compared to rilpivirine and doravirine. These dual‐target profiles suggest that AVG derivatives may function through both nucleoside‐ and non‐nucleoside‐like mechanisms. The distinct binding behaviors observed underscore the potential of AVG compounds as versatile antiviral agents capable of overcoming resistance. This study highlights AVG scaffolds as promising leads in next‐generation HIV therapeutics. This study is presented as an exploratory, in‐silico repurposing effort targeting HIV‐1 RT, and its findings should be validated through further in vitro and in vivo experiments, including RT polymerase assays, cell‐based HIV inhibition tests, and cytotoxicity evaluations.