FEP-Guided Selection of Bicyclic Heterocycles in Lead Optimization for Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase

• Published in: Journal of the American Chemical Society 2006-12, Vol.128 (48), p.15372-15373
• Main Authors: Kim, Joseph T, Hamilton, Andrew D, Bailey, Christopher M, Domoal, Robert A, Wang, Ligong, Anderson, Karen S, Jorgensen, William L
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Carbohydrates. Nucleosides and nucleotides; Chemistry; Drug Design; Exact sciences and technology; General and physical chemistry; HIV Reverse Transcriptase - antagonists & inhibitors; Models, Molecular; Molecular Structure; Nanostructures; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja066472g

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.