Fragment Based Approaches for Allosteric Metabotropic Glutamate Receptor (mGluR) Modulators.

Fragment Based Approaches for Allosteric Metabotropic Glutamate Receptor (mGluR) Modulators. Curr Top Med Chem. 2019 Aug 08;: Authors: Orgován Z, Ferenczy GG, Keserű GM Abstract 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 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 the current state of fragment based mGluR allosteric modulator research, and how this can contribute to the identification of new mGluR ligands with better activity and selectivity. PMID: 31393248 [PubMed - as supplied by publisher]
Source: Current Topics in Medicinal Chemistry - Category: Chemistry Authors: Tags: Curr Top Med Chem Source Type: research