Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 2 Magyar Tudosok Korutja, Budapest H-1117, Hungary.
Curr Top Med Chem. 2019;19(19):1768-1781. doi: 10.2174/1568026619666190808150039.
Metabotropic glutamate receptors (mGluR) are members of the class C G-Protein Coupled Receptors (GPCR-s) and have eight subtypes. These receptors are responsible for a variety of functions in the central and peripheral nervous systems and their modulation has therapeutic utility in neurological and psychiatric disorders. It was previously established that selective orthosteric modulation of these receptors is challenging, and this stimulated the search for allosteric modulators. Fragment-Based Drug Discovery (FBDD) is a viable approach to find ligands binding at allosteric sites owing to their limited size and interactions. However, it was also observed that the structure-activity relationship of allosteric modulators is often sharp and inconsistent. This can be attributed to the characteristics of the allosteric binding site of mGluRs that is a water channel where ligand binding is accompanied with induced fit and interference with the water network, both playing a role in receptor activation. In this review, we summarize fragment-based drug discovery programs on mGluR allosteric modulators and their contribution identifying of new mGluR ligands with better activity and selectivity.
代谢型谷氨酸受体（mGluR）是 C 类 G 蛋白偶联受体（GPCR-s）的成员，有 8 种亚型。这些受体负责中枢和外周神经系统的多种功能，其调节在神经和精神疾病中有治疗作用。以前已经确定，这些受体的选择性正构调节具有挑战性，这刺激了对变构调节剂的寻找。片段基药物发现（FBDD）是一种可行的方法，可以找到在变构位点结合的配体，因为它们的尺寸和相互作用有限。然而，也观察到变构调节剂的结构-活性关系通常很尖锐且不一致。这可以归因于 mGluR 的变构结合位点的特征，即配体结合伴随着诱导契合和对水网络的干扰，这两者都在受体激活中起作用。在这篇综述中，我们总结了 mGluR 变构调节剂的基于片段的药物发现计划及其对识别具有更好活性和选择性的新型 mGluR 配体的贡献。
