The reverse transcriptase (RT) enzyme is the prime target of nucleoside/ nucleotide (NRTI) and non-nucleoside (NNRTI) reverse transcriptase
inhibitors. Here we investigate the structural basis of effects of drug-resistance mutations in clade C RT using three-dimensional structural
modeling. Apropos the expectation was for unique mechanisms in clade C based on interactions with amino acids of p66 subunit in RT molecule.
3-D structures of RT with mutations found in sequences from 2 treatment naïve, 8 failed and one reference clade C have been modeled and
analyzed. Models were generated by computational mutation of available crystal structures of drug bound homologous RT. Energy minimization
of the models and the structural analyses were carried out using standard methods. Mutations at positions 75,101,118,190,230,238 and 318
known to confer drug resistance were investigated. Different mutations produced different effects such as alteration of geometry of the drugbinding
pocket, structural changes at the site of entry of the drug (into the active site), repositioning the template bases or by discriminating the
inhibitors from their natural substrates. For the mutations analyzed, NRTI resistance was mediated mainly by the ability to discriminate between
inhibitors and natural substrate, whereas, NNRTI resistance affected either the drug entry or the geometry of the active site. Our analysis
suggests that different mutations result in different structural effects affecting the ability of a given drug to bind to the RT. Our studies will help
in the development of newer drugs taking into account the presence of these mutations and the structural basis of drug resistance
