Inhibitor design by wrapping packing defects in HIV-1 proteins
Inhibitor design by wrapping packing defects in HIV-1 proteins
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DOI：
10.1073/pnas.0404641101
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发表时间：
2004-08-10
影响因子：
11.1
通讯作者：
Scheraga, HA
中科院分区：
文献类型：
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作者：
Fernández, A;Rogale, K;Scheraga, HA
两种病毒蛋白，HIV-1蛋白酶和HIV-1整合酶，已经被靶向用于抑制剂设计以防止HIV-1病毒体的组装和成熟。这些蛋白质的酶促机制涉及作为一般酸或碱的侧链基团。此外，催化活性要求从化学反应位点周围的微环境中除去水，或者限制水充当活化的亲核试剂。在这里，我们确定了以前未被认识的结构特征，促进水从极性催化区域的去除。以氢键形式存在的分子内脱水不足的包装缺陷（称为“非离子”）被策略性地放置在结构中以诱导无水酶途径。脱水子在进一步去溶剂化后变得静电增强和稳定。因此，包装缺陷与极性活性基团协同作用，以增强酶的静电。然而，由于双链体是粘性的，它们构成了抑制剂设计的靶标。我们注意到，抑制剂通过进一步去溶剂化配体而附着在极性表面上，从而阻断了活性位点或与利用底物有关的位点。因此，出于功能原因，需要使用这些工具，使其成为合适的目标。靶向HIV-1蛋白酶、猫免疫缺陷病毒蛋白酶和HIV-1整合酶时成功的差异在靶向分布方面得到合理化，揭示了靶向策略的可能改进。提出了设计优化的原则，以创建一个抑制剂，可以被中和，只有在催化功能的损失为代价。还讨论了使用包裹蛋白质的药物来阻断蛋白质-蛋白质缔合的可能性。
Two viral proteins, HIV-1 protease and HIV-1 integrase, have been targeted for inhibitor design to prevent assembly and maturation of HIV-1 virions. The enzymatic mechanism of these proteins involves side-chain groups that serve as general acids or bases. Furthermore, catalytic activity requires that water be removed from the microenvironment surrounding the chemical reaction site or be constrained to serve as an activated nucleophile. Here, we identify previously unrecognized structural features that promote water removal from polar catalytic regions. Packing defects in the form of hydrogen bonds that are insufficiently dehydrated intramolecularly, named "dehydrons," are strategically placed in the structure to induce an anhydrous enzymatic pathway. Dehydrons become electrostatically enhanced and stabilized upon further desolvation. Thus, packing defects act synergistically with the polar active groups to enhance the enzymatic electrostatics. However, because dehydrons are sticky, they constitute targets for inhibitor design. We noticed that inhibitors attach to polar surfaces by further desolvating dehydrons, thus blocking the active sites or the sites involved in harnessing the substrate. The dehydrons are thus required for functional reasons, making them suitable targets. The differences in success when targeting HIV-1 protease, feline immunodeficiency virus protease, and HIV-1 integrase are rationalized in terms of the dehydron distribution, revealing possible improvements in the targeting strategy. Principles of design optimization are proposed to create an inhibitor that can be neutralized only at the expense of the loss of catalytic function. The possibility of using drugs that wrap dehydrons to block protein-protein associations is also discussed.