Electronic Structure–Binding Affinity Correlation of Sulfur/Selenium-Modified AZT Derivatives Targeting HIV-1 M184V Reverse Transcriptase

Abstract

The emergence of drug resistance caused by mutations in HIV-1 reverse transcriptase (RT), particularly M184V, significantly compromises the clinical efficacy of nucleoside reverse transcriptase inhibitors such as azidothymidine (AZT). In this study, sulfur- and selenium-modified AZT derivatives were rationally designed to enhance electronic properties and improve binding performance against the HIV-1 M184V RT–DNA complex (PDB ID: 6UIR). A combined density functional theory (DFT) and molecular docking approach was employed to elucidate structure–activity relationships and identify key electronic determinants governing target recognition.

Frontier molecular orbital analysis reveals that compound 1 stands out with the smallest HOMO-LUMO gap, which means it’s the most reactive of the group. Its strong docking score and solid hydrogen bonding with the mutated active site back this up. Compound 3, on the other hand, has a bigger HOMO-LUMO gap. So, it’s more kinetically stable but doesn’t bind as well. What’s interesting is compound 2—a much higher dipole moment gives it better electrostatic complementarity and stronger stabilizing interactions with the M184V RT enzyme.

All in all, these results make it clear: electronic reactivity and molecular polarity matter a lot when you’re looking at how ligands interact with reverse transcriptase in drug-resistant variants. Knowing this gives researchers a smarter way to design second-generation AZT inhibitors that actually work against resistant forms of HIV.