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J Am Chem Soc. 2011 Oct 5;133(39):15686-96. doi: 10.1021/ja2058583. Epub 2011 Sep 9.

Efficient discovery of potent anti-HIV agents targeting the Tyr181Cys variant of HIV reverse transcriptase.

Author information

1
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States. william.jorgensen@yale.edu

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) that interfere with the replication of human immunodeficiency virus (HIV) are being pursued with guidance from molecular modeling including free-energy perturbation (FEP) calculations for protein-inhibitor binding affinities. The previously reported pyrimidinylphenylamine 1 and its chloro analogue 2 are potent anti-HIV agents; they inhibit replication of wild-type HIV-1 in infected human T-cells with EC(50) values of 2 and 10 nM, respectively. However, they show no activity against viral strains containing the Tyr181Cys (Y181C) mutation in HIV-RT. Modeling indicates that the problem is likely associated with extensive interaction between the dimethylallyloxy substituent and Tyr181. As an alternative, a phenoxy group is computed to be oriented in a manner diminishing the contact with Tyr181. However, this replacement leads to a roughly 1000-fold loss of activity for 3 (2.5 μM). The present report details the efficient, computationally driven evolution of 3 to novel NNRTIs with sub-10 nM potency toward both wild-type HIV-1 and Y181C-containing variants. The critical contributors were FEP substituent scans for the phenoxy and pyrimidine rings and recognition of potential benefits of addition of a cyanovinyl group to the phenoxy ring.

PMID:
21853995
PMCID:
PMC3183387
DOI:
10.1021/ja2058583
[Indexed for MEDLINE]
Free PMC Article

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