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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Review Article

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

Author(s): Zoltán Orgován, György G. Ferenczy and György M. Keserű*

Volume 19, Issue 19, 2019

Page: [1768 - 1781] Pages: 14

DOI: 10.2174/1568026619666190808150039

Price: $65


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.

Keywords: Metabotropic glutamate receptors, GPCR, Fragment-based drug discovery, Allosteric modulators, Glutamate binding site, Cysteine rich domain.

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