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

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

doi:10.1021/ja066472g

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

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

Chemistry

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	15372-15373
Number of pages	2
Journal	Journal of the American Chemical Society
Volume	128
Issue number	48
DOIs	https://doi.org/10.1021/ja066472g
State	Published - Dec 6 2006

ASJC Scopus subject areas

Catalysis
General Chemistry
Biochemistry
Colloid and Surface Chemistry

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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.",

author = "Kim, {Joseph T.} and Hamilton, {Andrew D.} and Bailey, {Christopher M.} and Domoal, {Robert A.} and Ligong Wang and Anderson, {Karen S.} and Jorgensen, {William L.}",

year = "2006",

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T1 - FEP-guided selection of bicyclic heterocycles in lead optimization for non-nucleoside inhibitors of HIV-1 reverse transcriptase

AU - Kim, Joseph T.

AU - Hamilton, Andrew D.

AU - Bailey, Christopher M.

AU - Domoal, Robert A.

AU - Wang, Ligong

AU - Anderson, Karen S.

AU - Jorgensen, William L.

PY - 2006/12/6

Y1 - 2006/12/6

N2 - 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.

AB - 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.

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JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

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ER -

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

Abstract

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