title: Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase.
abstract: Design principles are delineated for non-nucleoside inhibitors for HIV-1 reverse transcriptase (NNRTIs). Simultaneous optimization of binding affinity for wild-type RT, tolerance for viral mutations, and physical properties is pursued. Automated lead generation with the growing program BOMB, Monte Carlo simulations with free-energy perturbation theory for lead optimization, and property analysis with QikProp are featured. An initial 30 microM lead has been optimized rapidly to the 10 nM level.
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA. william.jorgensen@yale.edu
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.forename: Juliana
authors.initials: J
authors.lastname: Ruiz-Caro
authors.forename: Julian
authors.initials: J
authors.lastname: Tirado-Rives
authors.forename: Aravind
authors.initials: A
authors.lastname: Basavapathruni
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D017076:Computer-Aided Design; D024921:Drug Resistance, Multiple, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D009010:Monte Carlo Method; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase