Docking studies of some 5-hydroxypyridine-4-one derivatives: evaluation of integrase and ribonuclease H domain of reverse transcriptase as possible targets for anti-HIV-1 activity

Abstract

Anti-HIV-1 activity of a series of 5-hydroxypyridine-4-ones was evaluated using single-round HIV-1 infection assay. The first detailed molecular binding models for this scaffold interacting with the two metal-dependent viral enzyme in the retroviral life cycle, integrase, and RNase H were investigated. Docking models suggest that the chelating functionalities of the compounds interact with metal ions in a relatively hydrophilic region, anchoring the inhibitor onto the protein surface, whereas the lipophilic moieties fit in the hydrophobic cavities near the active site. Based on the obtained results, binding affinity of the molecules to the active site of both enzymes is strongly influenced by the presence of aromatic substituents or hydrophobic moieties on the main scaffold explaining the stronger and more effective in silico interactions of the 5-benzyloxy derivatives with protein-metal complex compared with free 5-hydroxyl derivatives. These findings may be useful information for the development of novel IN/RNase H dual inhibitors.