Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu5) X-ray Structures

John A. Christopher, Zoltán Orgován, Miles Congreve, Andrew S. Doré, James C. Errey, Fiona H. Marshall, Jonathan S. Mason, Krzysztof Okrasa, Prakash Rucktooa, Maria J. Serrano-Vega, G. Ferenczy, György M. Keseru

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Two interesting new X-ray structures of negative allosteric modulator (NAM) ligands for the mGlu5 receptor, M-MPEP (3) and fenobam (4), are reported. The new structures show how the binding of the ligands induces different receptor water channel conformations to previously published structures. The structure of fenobam, where a urea replaces the acetylenic linker in M-MPEP and mavoglurant, reveals a binding mode where the ligand is rotated by 180° compared to a previously proposed docking model. The need for multiple ligand structures for accurate GPCR structure-based drug design is demonstrated by the different growing vectors identified for the head groups of M-MPEP and mavoglurant and by the unexpected water-mediated receptor interactions of a new chemotype represented by fenobam. The implications of the new structures for ligand design are discussed, with extensive analysis of the energetics of the water networks of both pseudoapo and bound structures providing a new design strategy for allosteric modulators.

Original languageEnglish
Pages (from-to)207-222
Number of pages16
JournalJournal of Medicinal Chemistry
Volume62
Issue number1
DOIs
Publication statusPublished - Oct 1 2019

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Metabotropic Glutamate 5 Receptor
G-Protein-Coupled Receptors
X-Rays
Ligands
Aquaporins
Water
Drug Design
Urea
Head
fenobam

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators : A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu5) X-ray Structures. / Christopher, John A.; Orgován, Zoltán; Congreve, Miles; Doré, Andrew S.; Errey, James C.; Marshall, Fiona H.; Mason, Jonathan S.; Okrasa, Krzysztof; Rucktooa, Prakash; Serrano-Vega, Maria J.; Ferenczy, G.; Keseru, György M.

In: Journal of Medicinal Chemistry, Vol. 62, No. 1, 01.10.2019, p. 207-222.

Research output: Contribution to journalArticle

Christopher, John A. ; Orgován, Zoltán ; Congreve, Miles ; Doré, Andrew S. ; Errey, James C. ; Marshall, Fiona H. ; Mason, Jonathan S. ; Okrasa, Krzysztof ; Rucktooa, Prakash ; Serrano-Vega, Maria J. ; Ferenczy, G. ; Keseru, György M. / Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators : A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu5) X-ray Structures. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 1. pp. 207-222.
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