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

被引：77

作者：

Kim, Joseph T.

Hamilton, Andrew D.

Bailey, Christopher M.

Domoal, Robert A.

Wang, Ligong

Anderson, Karen S.

Jorgensen, William L.

机构：

[1] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA

[2] Yale Univ, Dept Chem, New Haven, CT 06520 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2006年 / 128卷 / 48期

关键词：

D O I：

10.1021/ja066472g

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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. Copyright © 2006 American Chemical Society.

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页码：15372 / 15373

页数：2

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