title: FEP-guided selection of bicyclic heterocycles in lead optimization for non-nucleoside inhibitors of HIV-1 reverse transcriptase.
abstract: Monte Carlo simulations using free energy perturbation theory have been used to guide the selection of bicyclic heterocycles in the lead optimization of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Good correlation is found between predicted and observed activities. Six compounds are reported with EC50 values below 20 nM for protection of human MT-2 cells against the cytopathogenicity of HIV-1. Striking variation in activity is found and analyzed for an isomeric pyrrolopyrimidine and pyrrolopyrazine pair.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Kim
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bailey
authors.forename: Robert A
authors.initials: RA
authors.lastname: Domaoal
authors.forename: Robert A
authors.initials: RA
authors.lastname: Domoal
authors.forename: Ligong
authors.initials: L
authors.lastname: Wang
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D049329:Nanostructures; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase