Molecular Modeling of Potential Dual Inhibitors of HIV Reverse Transcriptase and Integrase

Abstract

With the goal of suggesting dual inhibitors of HIV reverse transcriptase (RT) and integrase (IN), herein we report the molecular docking of an initial set of 556 compounds related to the pyridinone class. Docking with multiple crystallographic structures of HIV-1 RT led to 160 potential binders of RT interacting with key amino acid residues at the enzyme’s allosteric site. Compounds selected from the docking with RT were further docked with a crystallographic structure of HIV-1 IN. A total of 31 structures had the potential to make contacts with Mg2+ ions located in a small space between DNA and IN. Interactions with Mg2+ ions are relevant because they participate in the stabilization of the IN-DNA complex. In conclusion, 31 compounds synthetically accessible are proposed as dual inhibitors of RT and IN. It is hypothesized that the suggested compounds will inhibit RT by occupying the allosteric site for NNRTIs and will inhibit the catalytic activity of IN by destabilizing the IN-DNA complex. The main perspective of this work is the synthesis and biological testing of the candidate molecules.