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

Joseph T. Kim, Andrew Hamilton, Christopher M. Bailey, Robert A. Domoal, Ligong Wang, Karen S. Anderson, William L. Jorgensen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)15372-15373
Number of pages2
JournalJournal of the American Chemical Society
Volume128
Issue number48
DOIs
StatePublished - Dec 6 2006

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Polytetrafluoroethylene
Free energy
HIV-1
Lead
Human immunodeficiency virus 1 reverse transcriptase
Monte Carlo simulation
pyrrolopyrimidine

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

FEP-guided selection of bicyclic heterocycles in lead optimization for non-nucleoside inhibitors of HIV-1 reverse transcriptase. / Kim, Joseph T.; Hamilton, Andrew; Bailey, Christopher M.; Domoal, Robert A.; Wang, Ligong; Anderson, Karen S.; Jorgensen, William L.

In: Journal of the American Chemical Society, Vol. 128, No. 48, 06.12.2006, p. 15372-15373.

Research output: Contribution to journalArticle

Kim, Joseph T. ; Hamilton, Andrew ; Bailey, Christopher M. ; Domoal, Robert A. ; Wang, Ligong ; Anderson, Karen S. ; Jorgensen, William L. / FEP-guided selection of bicyclic heterocycles in lead optimization for non-nucleoside inhibitors of HIV-1 reverse transcriptase. In: Journal of the American Chemical Society. 2006 ; Vol. 128, No. 48. pp. 15372-15373.
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AU - Anderson, Karen S.

AU - Jorgensen, William L.

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