Single-Molecule Pulling Simulations Can Discern Active from Inactive Enzyme Inhibitors
Single-Molecule Pulling Simulations Can Discern Active from Inactive Enzyme Inhibitors
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DOI：
10.1021/ja100259r
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发表时间：
2010-06-02
影响因子：
15
通讯作者：
Cavalli, Andrea
中科院分区：
文献类型：
--
作者：
Colizzi, Francesco;Perozzo, Remo;Cavalli, Andrea
了解配体蛋白质的识别和相互作用过程是基于结构的药物设计的首要任务。传统上，结合对接和分子动力学（MD）模拟的几种方法已被利用来研究药物感兴趣的复合物的物理化学性质。即使一个模型化的蛋白质配体复合物的几何性质可以很好地预测的计算方法，它是具有挑战性的排名一系列类似物在一个一致的方式与生物数据。在恶性疟原虫独特的β-羟酰基-ACP脱氢酶（PfFabZ）中，标准分子对接和MD模拟的应用部分足以揭示先前发现的抑制剂的活性。补充对接结果与原子模拟的转向分子动力学（SMD）框架，我们设计了一个在硅片上的方法来研究分子间的相互作用，并比较配体类似物的结合特性。我们假设了一个相互作用模型，既解释了已知配体的生物活性，又为设计新型酶抑制剂提供了见解。模仿单分子拉伸实验，我们使用SMD衍生的力曲线来区分活性和非活性化合物。设计了一种新的化合物，并预测了其对PfFabZ酶的生物活性。最后，实验证实了计算预测，突出了本文提出的药物设计方法的鲁棒性。
Understanding ligand protein recognition and interaction processes is of primary importance for structure-based drug design. Traditionally, several approaches combining docking and molecular dynamics (MD) simulations have been exploited to investigate the physicochemical properties of complexes of pharmaceutical interest. Even if the geometric properties of a modeled protein ligand complex can be well predicted by computational methods, it is challenging to rank a series of analogues in a consistent fashion with biological data. In the unique beta-hydroxyacyl-ACP dehydratase of Plasmodium falciparum (PfFabZ), the application of standard molecular docking and MD simulations was partially sufficient to shed light on the activity of previously discovered inhibitors. Complementing docking results with atomistic simulations in the steered molecular dynamics (SMD) framework, we devised an in silico approach to study molecular interactions and to compare the binding characteristics of ligand analogues. We hypothesized an interaction model that both explained the biological activity of known ligands, and provided insight into designing novel enzyme inhibitors. Mimicking single-molecule pulling experiments, we used SMD-derived force profiles to discern active from inactive compounds for the first time. A new compound was designed and its biological activity toward the PfFabZ enzyme predicted. Finally, the computational predictions were experimentally confirmed, highlighting the robustness of the drug design approach presented herein.