Exploring the role of receptor flexibility in structure-based drug discovery.
Exploring the role of receptor flexibility in structure-based drug discovery.
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DOI：
10.1016/j.bpc.2013.10.007
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发表时间：
2014-02
影响因子：
3.8
通讯作者：
McCammon, J. Andrew
中科院分区：
文献类型：
--
作者：
Feixas, Ferran;Lindert, Steffen;Sinko, William;McCammon, J. Andrew
关键词：
正确理解药物靶标中发生的生物分子识别机制对于提高药物发现和开发的效率至关重要。蛋白质的内在动力学特性对生物分子识别机制有很大的影响，构象选择等模型已被广泛用于解释这种动态缔合过程。然而，在与其他分子缔合之前和缔合之后在受体中发生的构象变化是多样的，并且当仅可获得受体的少数结构时不明显预测。鉴于蛋白质的灵活性在配体结合中的突出作用及其对药物发现的影响，在开始合理的药物设计工作之前，确定在生物分子识别中起主要作用的受体构象是非常有趣的。在这篇综述中，我们讨论了一些最近的进展，计算机辅助药物发现技术已被提出将受体的灵活性纳入基于结构的药物设计。由计算技术如分子动力学模拟或增强的采样技术提供的受体灵活性的允许有助于提高用于估计结合亲和力的方法的准确性，因此，这样的方法可以有助于发现新的药物先导物。
The proper understanding of biomolecular recognition mechanisms that take place in a drug target is of paramount importance to improve the efficiency of drug discovery and development. The intrinsic dynamic character of proteins has a strong influence on biomolecular recognition mechanisms and models such as conformational selection have been widely used to account for this dynamic association process. However, conformational changes occurring in the receptor prior and upon association with other molecules are diverse and not obvious to predict when only a few structures of the receptor are available. In view of the prominent role of protein flexibility in ligand binding and its implications for drug discovery, it is of great interest to identify receptor conformations that play a major role in biomolecular recognition before starting rational drug design efforts. In this review, we discuss a number of recent advances in computer-aided drug discovery techniques that have been proposed to incorporate receptor flexibility into structure-based drug design. The allowance for receptor flexibility provided by computational techniques such as molecular dynamics simulations or enhanced sampling techniques helps to improve the accuracy of methods used to estimate binding affinities and, thus, such methods can contribute to the discovery of novel drug leads.
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DOI：
10.1073/pnas.57.2.335
发表时间：
1967-01-01
影响因子：
11.1
作者：
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影响因子：
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