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