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

• Published in: Journal of the American Chemical Society 2011-10, Vol.133 (39), p.15686-15696
• Main Authors: Jorgensen, William L, Bollini, Mariela, Thakur, Vinay V, Domaoal, Robert A, Spasov, Krasimir A, Anderson, Karen S
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Anti-HIV Agents - chemistry; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Drug Discovery; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - genetics; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - enzymology; Inhibitory Concentration 50; Models, Molecular; Molecular Targeted Therapy; Nitriles - chemistry; Protein Conformation; Pyrimidines - chemistry; Structure-Activity Relationship; Thermodynamics; Triazines - chemistry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja2058583

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.