Comparative Studies on Inhibitors of HIV Protease: A Target for Drug Design

摘要

Bioinformatics tools are employed lately for in silico structure-function analysis of proteins. HIV proteaseinhibitors nelfinavir and tipranavir belong to the extended multi-ring systems. The intermolecular interactions made by thefunctional groups of the different residues on the protein molecule are probed with the help of computational tools for proteinhomology studies so as to identify the functional residues, create single, double, triple mutations using, different bioinformaticsservers and to observe the changes brought therein by docking. BLAST, RosettaDesign, PatchDock, Chimera were used in thepresent study for identifying the inhibitors as better drug targets. The HIV protease-nelfinavir complex (PDB code: IOHR)and HIV protease V82F/I84V double mutant-tipranavir complex (PDB code: 1D4S) were used as templates for introducingmutations on the HIV protease active site. In this study a structure-based computer-assisted search for the comparison of thetwo inhibitors of HIV protease was carried out. The results suggest that the two inhibitors nelfinavir and tipranavir could beused for treatment of AIDS by targeting the enzyme HIV protease as neither of the two inhibitors exhibit any cross-reactivitywith other human proteins, they readily bind to the mutated enzyme active site and still remain linked with the enzyme-substratecomplex in the presence of water molecules. The inhibitor nelfinavir undergoes several changes in hydrogen bonds formationwith the introduction of mutations on the HIV protease active site. It either has a positive or a negative inhibitory effect onHIV protease and forms new hydrogen bonds with a shorter bond lengths. Nelfinavir also seems to be an inhibitor of a morenarrow specificity as it shows changes in binding bringing thereby conformational changes in the native enzyme. Tipranavir onthe other hand seems to be a broad specificity inhibitor as no changes in the bond lengths with the introduction of mutationsare observed. Of the two inhibitors tipranavir could be targeted more effectively for designing future drug analogues as it isless vulnerable to mutations. The HIV mutants reported herein could also be used for preliminary identification of specificinhibitors as drugs that may alter the HIV protease activity for medicinal use.