Molecular mechanics analysis of drug-resistant mutants of HIV protease

Drug-resistant mutants of HIV-1 protease limit the long-termeffectiveness of current anti-viral therapy. In order to studydrug resistance, the wild-type HIV-1 protease and the mutantsR8Q, V32I, M46I, V82A, V82I, V82F, I84V, V32I/I84V and M46I/I84Vwere modeled with the inhibitors saquinavir and indinavir usingthe program AMMP. A new screen term was introduced to reproducemore correctly the electron distribution of atoms. The atomicpartial charge was represented as a delocalized charge distributioninstead of a point charge. The calculated protease–saquinavirinteraction energies showed the highly significant correlationof 0.79 with free energy differences derived from the measuredinhibition constants for all 10 models. Three different protonationstates of indinavir were evaluated. The best indinavir modelincluded a sulfate and gave a correlation coefficient of 0.68between the calculated interaction energies and free energiesfrom inhibition constants for nine models. The exception wasR8Q with indinavir, probably due to differences in the solvationenergy. No significant correlation was found using the standardmolecular mechanics terms. The incorporation of the new screencorrection resulted in better prediction of the effects of inhibitorson resistant protease variants and has potential for selectingmore effective inhibitors for resistant virus.