Heifetz Alexander, James Tim, Morao Inaki, Bodkin Michael J, Biggin Philip C
Evotec Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
Evotec Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
Curr Opin Pharmacol. 2016 Oct;30:14-21. doi: 10.1016/j.coph.2016.06.004. Epub 2016 Jul 13.
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.
G蛋白偶联受体（GPCR）建模方法在药物发现的从苗头化合物到先导化合物以及先导化合物优化阶段中被广泛应用。涉及分子动力学模拟的现代方案能够解决诸如结合自由能（亲和力）、配体诱导的GPCR灵活性、配体结合动力学、保守水的位置及其在配体结合中的作用以及突变影响等关键问题。这些计算的目标是预测现有配体与其受体之间复合物的结构，理解关键相互作用，并将这些见解应用于设计具有改善的结合、选择性或其他药理特性的新分子。在本综述中，我们通过一个分层GPCR建模方案及其在三个工业药物发现项目中的前瞻性应用，简要概述了各种计算方法。
