Active site binding modes of HIV-1 reverse transcriptase inhibitors from natural products

Abstract

Using the crystal structure of the complex of. HIV-1 reverse transcriptase catalytic core domain with an inhibitor bound to the active site, structural models for the interaction of various natural products with HIV-1 reverse transcriptase were generated by computational docking. The ligands from natural products and nevirapine are found to bind preferably in similar ways at active site. The binding site is formed by residues 100-103, 106, 181, 188, 227, 229, 234 and 235. The coherent picture of possible interactions of natural products at the active site provides an improved basis for structure-based ligand design. The hydrophobic interaction at the hydrophobic pocket, hydrogen bond interaction with the Lys103 and 101 and the angle between systems of ligand which should be in the range of 108-115° are suggested to be of prime importance. Although, costatolide and 4' ,6'-dihydroxyavarone are not able to form hydrogen bonds with Lys103, they do show tight binding with HIV-1 reverse transcriptase enzyme. Therefore, in the situation that Lys103 is mutated which usually occurs during treatment with nevirapine, costatolide and 4',6' -dihydroxyavarone are still effective. This leads to the further development of these two compounds as" non-nucleoside reverse transcriptase inhibitors (NNRTls) for the treatment of the nevirapine-resistant HIV-1 strains.