Computational Study of the Resistance Shown by the Subtype B/HIV-1 Protease to Currently Known Inhibitors
Computational Study of the Resistance Shown by the Subtype B/HIV-1 Protease to Currently Known Inhibitors
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DOI：
10.1021/bi100569u
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发表时间：
2010-05-18
期刊：
影响因子：
2.9
通讯作者：
Colombo, Giorgio
中科院分区：
文献类型：
--
作者：
Genoni, Alessandro;Morra, Giulia;Colombo, Giorgio
人类免疫缺陷病毒1型蛋白酶（HIV-1 PR）是HIV-1生命周期中的必需酶。因此，这种蛋白质代表了艾滋病治疗中的主要药物靶标，但由高病毒突变率引起的对抗逆转录病毒抑制剂鸡尾酒的新抗性代表了艾滋病治疗中的重大挑战。许多突变不位于活性位点或结合口袋内，也不显著改变酶的三维结构组织;因此，它们改变抑制剂对蛋白酶亲和力的机制仍不确定。在这篇文章中，我们提出了一个全原子计算分析的活性位点残基和其余的蛋白质和不同的HIV-1 PR复合物的能量特性之间的动态残基-残基协调。我们分析了野生型形式和突变形式，诱导耐药性，特别是，结果显示野生型和突变体之间的差异，在其机制的动态协调，在信号传播之间的活性位点残基和其余的蛋白质，并在能源网络负责稳定的约束抑制剂构象。最后，我们对HIV-1蛋白酶耐药性提出了一个动态和充满活力的解释，并且通过这个模型，我们确定了一个可能的新位点，这可能有助于设计新的HIV-1 PR变构抑制剂家族。
Human immunodeficiency virus type 1 protease (HIV-1 PR) is an essential enzyme in the HIV-1 life cycle. As such, this protein represents a major drug target in AIDS therapy, but emerging resistance to antiretroviral inhibitor cocktails, caused by high viral mutation rates, represents a significant challenge in AIDS treatment. Many mutations are not located within the active site or binding pocket, nor they do significantly modify the three-dimensional structural organization of the enzyme; hence, the mechanism(s) by which they alter inhibitor affinity for the protease remains uncertain. In this article, we present an all-atom computational analysis of the dynamic residue-residue coordination between the active site residues and the rest of the protein and of the energetic properties of different HIV-1 PR complexes. We analyze both the wildtype form and mutated forms that induce drug resistance, In particular, the results show differences between the wild type and the mutants in their mechanism of dynamic coordination, in the signal propagation between the active site residues and the rest of the protein, and in the energy networks responsible for the stabilization of the bound inhibitor conformation. Finally, we propose a dynamic and energetic explanation for HIV-1 protease drug resistance, and, through this model, we identify a possible new site that could be helpful in the design of a new family of HIV-1 PR allosteric inhibitors.