title: 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.
authors.affiliation: NCI-Frederick, Frederick, MD 21702, USA. mcsmith@mcdaniel.edu
authors.forename: Marilyn B Kroeger
authors.initials: MB
authors.lastname: Smith
authors.forename: Sandra
authors.initials: S
authors.lastname: Ruby
authors.forename: Stanislav
authors.initials: S
authors.lastname: Horouzhenko
authors.forename: Bryan
authors.initials: B
authors.lastname: Buckingham
authors.forename: Julia
authors.initials: J
authors.lastname: Richardson
authors.forename: Ina
authors.initials: I
authors.lastname: Puleri
authors.forename: Emily
authors.initials: E
authors.lastname: Potts
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.forename: Edward
authors.initials: E
authors.lastname: Arnold
authors.forename: Wanyi
authors.initials: W
authors.lastname: Zhang
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Michejda
authors.forename: Richard H
authors.initials: RH
authors.lastname: Smith
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D030562:Databases, Protein; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D016014:Linear Models; D008958:Models, Molecular; D009010:Monte Carlo Method; D009154:Mutation; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase