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首页> 外文期刊>AIDS Research and Human Retroviruses >Positional adaptability in the design of mutation-resistant nonnucleoside HIV-1 reverse transcriptase inhibitors: A supramolecular perspective
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Positional adaptability in the design of mutation-resistant nonnucleoside HIV-1 reverse transcriptase inhibitors: A supramolecular perspective

机译：突变抗性非核苷HIV-1逆转录酶抑制剂设计中的位置适应性：超分子观点

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摘要

Drug resistance is a key cause of failed treatment of HIV infection. The efficacy of nonnucleoside reverse transcriptase-inhibiting (NNRTI) drugs is impaired by the rapid emergence of drug-resistant mutations. The literature supports the idea that purposefully designed flexible NNRTIs at an active site may help overcome drug resistance. It is proposed here that the usual "lock and key" model, with respect to NNRTI drug design, be expanded to consider creating "master keys" that would automatically adjust conformations to fit all of the "locks" mutations may make. The present work introduces the novel perspective of designing and creating supramolecular assemblies as potential NNRTIs (instead of the relatively more rigid single-molecule inhibitors). Specifically, flexible self-assembling quinhydrone supramolecular dimers formed from quinonoid monomers (designed to be highly flexible NNRTIs themselves) will be offered as a working example of this new perspective in NNRTI drug design. Quinonoid compounds have demonstrated binding interactions at various sites of the HIV-1 RT enzyme, including the elusive ribonuclease H area. Quinhydrone self-organized dimers have at some point in their molecular architecture a noncovalently interacting donor-acceptor ring pair complex. This complex is at the heart of the increased torsional, rotational, and translational motion this species will experience at a particular active site. Flexible supramolecular assemblies, together with their flexible monomer components, may offer a critical advantage in retaining potency against a wide range of drug-resistant HIV-1 RTs. This new supramolecular perspective may also have broader implications in the general field of antimicrobial drug design.
机译：耐药性是治疗HIV感染失败的关键原因。非核苷逆转录酶抑制（NNRTI）药物的功效因耐药突变的迅速出现而受到损害。文献支持这样的想法，即在活动部位故意设计柔性NNRTIs可能有助于克服耐药性。这里提出，关于NNRTI药物设计，通常的“锁和钥匙”模型被扩展以考虑创建“主钥匙”，该主钥匙将自动调整构象以适合所有“锁”突变。本工作介绍了设计和创建超分子组件作为潜在的NNRTIs（而不是相对更刚性的单分子抑制剂）的新颖观点。具体而言，将提供由醌类单体形成的柔性自组装醌氢超分子二聚体（设计为高度柔性的NNRTIs本身），作为NNRTI药物设计中这一新观点的工作实例。醌类化合物已证明在HIV-1 RT酶的多个位点（包括难以捉摸的核糖核酸酶H区域）具有结合相互作用。喹hydr酮自组织二聚体在分子结构中的某个点具有非共价相互作用的供体-受体环对复合物。这种复合体是该物种在特定活动部位经历的增加的扭转，旋转和平移运动的核心。柔性超分子组装体及其柔性单体组分可在保持针对各种耐药HIV-1 RT的效力方面提供关键优势。这种新的超分子观点也可能在抗菌药物设计的一般领域中产生更广泛的影响。

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