HIV-1 Reverse Transcriptase Variants: Molecular Modeling of Y181C, V106A, L100I, and K103N Mutations with Nonnucleoside Inhibitors Using Monte Carlo Simulations in Combination with a Linear Response Method

Abstract

The energies and physical descriptors for the binding of 21 novel 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-benzimidazole (BPBI) analogs to HIV-1 reverse transcriptase (RT) variants Y181C, L100I, V106A, and K103N have been determined using Monte Carlo (MC) simulations. The crystallographic structure of the lead compound, 4-methyl BPBI, was used as a starting point to model the inhibitors in both the mutant bound and the unbound states. The energy terms and physical descriptors obtained from the calculations were reasonably correlated with the respective experimental EC50 values for the inhibitors against the various mutant RTs. Using the linear response correlations from the calculations, 2 novel BPBI inhibitors have been designed and simulations have been carried out. The results show the computed deltaG(binding) values match the experimental data for the analogs. Given the ongoing problem with drug resistance, the ability to predict the activity of novel analogs against variants prior to synthesis is highly advantageous.

High Potency of Indolyl Aryl Sulfone Nonnucleoside Inhibitors towards Drug-Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutants Is Due to Selective Targeting of Different Mechanistic Forms of the Enzyme

“…Because of the different chemical and structural features of the inhibitors and the side chain flexibility, the bound NNBS adopts different conformations (28). Moreover, mutations of some amino acids cause variation of the NNBS properties, thus decreasing affinities of most of the inhibitors (12,24,25). In particular, the NNRTI resistance mutations Tyr188Leu and Tyr181Ile/Cys reduce -interactions, the Gly190Ala mutation leads to a smaller active site space because of a steric conflict between the methyl side chain and the inhibitor, and the formation of an additional hydrogen bond when amino acid 103 is mutated from Lys to Asn reduces inhibitor entrance into the NNBS.…”