Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. 1.
Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. 1.
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DOI：
10.1021/jm040071z
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发表时间：
2004-11-18
影响因子：
7.3
通讯作者：
Stammers, DK
中科院分区：
文献类型：
--
作者：
Hopkins, AL;Ren, JS;Stammers, DK
我们使用基于结构的方法设计了一系列新的HIV-1RT非核苷抑制剂(NNRTIs)。对HIV-1 RT-NNRTI复合体的广泛晶体结构的详细分析以及耐药突变的数据已经确定了抑制物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的喹诺酮类NNRTI。其中四个化合物的晶体结构分析证实了预测的结合模式。这个喹诺酮系列的成员保持了对RT中重要的Tyr181Cys和Leu100Ile耐药突变的高活性。
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.