FEP-guided selection of bicyclic heterocycles in lead optimization for non-nucleoside inhibitors of HIV-1 reverse transcriptase

J Am Chem Soc. 2006 Dec 6;128(48):15372-3. doi: 10.1021/ja066472g.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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
  • Drug Design
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Structure
  • Nanostructures
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology

Substances

  • Anti-HIV Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase