MOLECULAR MODELING OF HIV-1 REVERSE-TRANSCRIPTASE DRUG-RESISTANT MUTANT STRAINS - IMPLICATIONS FOR THE MECHANISM OF POLYMERASE ACTION

A computer model of human immunodeficiency virus type 1 (HIV-1) revers e transcriptase (RT) either alone, or complexed with a non-nucleoside inhibitor (NNI), was constructed using crystal coordinate data from a subset of the protein surrounding the binding pocket region. Molecular mechanics calculations were carried out on solvated wild-type RT and RT that contained modifications corresponding to resistance-engenderin g mutations. Results from the calculations revealed that the r.m.s. di fference between 12 modified proteins and that of wild-type RT could b e qualitatively correlated with the measured polymerase activity of th e enzyme in the presence of these mutations. In addition, the level of activity was related to the measured distance between the primer grip and dNTP binding regions of the protein. These data suggest a direct correlation between RT structure and function. Complexes of RT-8-C1 TI BO and RT-alpha-APA were also minimized in models containing modificat ions corresponding to key drug-resistant mutants. The variant complexe s all showed weaker binding than wild-type RT, while giving rise to si milar, but critical changes in the protein. Therefore, the design of n ew inhibitors should center on obtaining stronger binding drugs to key drug-resistant RT variants.