Hopkins Andrew L, Ren Jingshan, Milton John, Hazen Richard J, Chan Joseph H, Stuart David I, Stammers David K
Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
J Med Chem. 2004 Nov 18;47(24):5912-22. doi: 10.1021/jm040071z.
We have used a structure-based approach to design a novel series of non-nucleoside inhibitors of HIV-1 RT (NNRTIs). Detailed analysis of a wide range of crystal structures of HIV-1 RT-NNRTI complexes together with data on drug resistance mutations has identified factors important for tight binding of inhibitors and resilience to mutations. Using this approach we have designed and synthesized a novel series of quinolone NNRTIs. Crystal structure analysis of four of these compounds in complexes with HIV-1 RT confirms the predicted binding modes. Members of this quinolone series retain high activity against the important resistance mutations in RT at Tyr181Cys and Leu100Ile.
我们采用了基于结构的方法来设计一系列新型的HIV-1逆转录酶非核苷抑制剂（NNRTIs）。对大量HIV-1逆转录酶-NNRTI复合物晶体结构的详细分析以及耐药性突变数据，确定了抑制剂紧密结合和抗突变能力的重要因素。利用这种方法，我们设计并合成了一系列新型喹诺酮类NNRTIs。其中四种化合物与HIV-1逆转录酶复合物的晶体结构分析证实了预测的结合模式。该喹诺酮系列成员对逆转录酶中Tyr181Cys和Leu100Ile的重要耐药性突变仍保持高活性。
