Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants
Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants
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DOI：
10.1021/jm030558s
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发表时间：
2004-05-06
影响因子：
7.3
通讯作者：
Arnold, E
中科院分区：
文献类型：
--
作者：
Das, K;Clark, AD;Arnold, E
抗艾滋病候选药物和非核苷类逆转录酶抑制剂（NNRTI）TMC 125-R165335（依曲韦林）引起的病毒载量的初始下降与在初治患者中观察到的五种药物组合相似，并在感染NNRTI耐药HIV-1变异体的患者中保持效力。TMC 125-R165335和相关的抗艾滋病候选药物可以以多种构象结合酶RT，从而逃避耐药性突变的影响。结构研究表明，这种抑制剂和其他二芳基嘧啶（DAPY）类似物可以通过几种方式适应NNRTI结合口袋的变化：（1）DAPY类似物可以以至少两种构象不同的模式结合;（2）在给定的结合模式内，扭转柔性DAPY类似物的构象变化（“摆动”）允许获得许多构象变体;和（3）DAPY类似物的紧凑设计允许在囊袋内显著的重新定位和重新定向（平移和旋转）（“抖动”）。这种适应似乎是至关重要的效力对野生型和广泛的耐药突变体HIV-1 RT。利用抑制剂构象灵活性的有利组分（例如关于战略性定位的化学键的扭转灵活性）可以是强大的药物设计概念，特别是对于设计将有效对抗快速突变的靶标的药物。
Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naive patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1) DAPY analogues can bind in at least two conformationally distinct modes; (2) within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3) the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.