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

Zoltán Orgován, György G. Ferenczy, György M. Keserű

Research output: Contribution to journalReview article

1 Citation (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1768-1781
Number of pages14
JournalCurrent topics in medicinal chemistry
Volume19
Issue number19
DOIs
Publication statusPublished - Jan 1 2019

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Keywords

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

ASJC Scopus subject areas

  • Drug Discovery

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