Guiding lead optimization with GPCR structure modeling and molecular dynamics
Guiding lead optimization with GPCR structure modeling and molecular dynamics
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DOI：
10.1016/j.coph.2016.06.004
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发表时间：
2016-10-01
影响因子：
4
通讯作者：
Biggin, Philip C.
中科院分区：
文献类型：
--
作者：
Heifetz, Alexander;James, Tim;Biggin, Philip C.
G蛋白偶联受体（GPCR）建模方法广泛用于药物发现的先导物命中和先导物优化阶段。涉及分子动力学模拟的现代方案可以解决关键问题，例如结合自由能（亲和力），配体诱导的GPCR灵活性，配体结合动力学，保守的水位置及其在配体结合中的作用和突变的影响。这些计算的目标是预测现有配体及其受体之间的复合物的结构，了解关键的相互作用，并利用这些见解设计具有改进的结合，选择性或其他药理学性质的新分子。在这篇综述中，我们提出了一个简短的调查，说明通过分层GPCR建模协议和其在三个工业药物发现项目的应用前景的各种计算方法。
G-protein coupled receptor (GPCR) modeling approaches are widely used in the hit-to-lead and lead optimization stages of drug discovery. Modern protocols that involve molecular dynamics simulation can address key issues such as the free energy of binding (affinity), ligand-induced GPCR flexibility, ligand binding kinetics, conserved water positions and their role in ligand binding and the effects of mutations. The goals of these calculations are to predict the structures of the complexes between existing ligands and their receptors, to understand the key interactions and to utilize these insights in the design of new molecules with improved binding, selectivity or other pharmacological properties. In this review we present a brief survey of various computational approaches illustrated through a hierarchical GPCR modeling protocol and its prospective application in three industrial drug discovery projects.