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

被引:61
作者
Jorgensen, William L. [1 ]
Bollini, Mariela [1 ]
Thakur, Vinay V. [1 ]
Domaoal, Robert A. [2 ]
Spasov, Krasimir A. [2 ]
Anderson, Karen S. [2 ]
机构
[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA
基金
美国国家卫生研究院;
关键词
ENERGY PERTURBATION CALCULATIONS; NONNUCLEOSIDE INHIBITORS; CRYSTAL-STRUCTURE; OPTIMIZATION; VIRUS; DRUG; DESIGN; RESISTANCE; ENERGETICS; RESOLUTION;
D O I
10.1021/ja2058583
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 mu M). 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.
引用
收藏
页码:15686 / 15696
页数:11
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