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Efficient Discovery of Potent Anti-HIV Agents Targeting the Tyr181Cys Variant of HIV Reverse Transcriptase

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William L. Jorgensen*†, Mariela Bollini†, Vinay V. Thakur†, Robert A. Domaoal‡, Krasimir A. Spasov‡, and Karen S. Anderson*‡

Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States

J. Am. Chem. Soc., 2011, 133 (39), pp 15686–15696

DOI: 10.1021/ja2058583

Publication Date (Web): August 19, 2011

karen.anderson@yale.edu; william.jorgensen@yale.edu

Section:

Pharmacology

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 EC₅₀ 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.

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