mGluR5: Exploration of Orthosteric and Allosteric Ligand Binding Pockets and Their Applications to Drug Discovery

Abstract

Since its discovery in 1992, mGluR5 has attracted significant attention and been linked to several neurological and psychiatric diseases. Ligand development was initially focused on the orthosteric binding pocket, but lack of subtype selective ligands changed the focus to the transmembrane allosteric binding pocket. This strategy has resulted in several drug candidates in clinical testing. In the present article we explore the orthosteric and allosteric binding pockets in terms of structure and ligand recognition across the mGluR subtypes and groups, and discuss the clinical potential of ligands targeting these pockets. We have performed binding mode analyses of non- and group-selective orthosteric ligands based on molecular docking in mGluR crystal structures and models. For the analysis of the allosteric binding pocket we have combined data from all mGluR5-mutagenesis studies, collectively reporting five negative allosteric modulators and 47 unique mutations, and compared it to the closest related homolog, mGluR1.

Therapeutic Molecules and Endogenous Ligands Regulate the Interaction between Brain Cellular Prion Protein (PrPC) and Metabotropic Glutamate Receptor 5 (mGluR5)

“…Also, DHPG failed to modulate the coimmunoprecipitation of PrP C and Myc-mGluR-N8/C5. These findings provide evidence for the drug specificity in the assays we developed because the Myc-mGluR-N5/C8 mutant protein does not contain the transmembrane-spanning part of mGluR5 that is targeted by MTEP (61). DHPG, on the other hand, is highly specific for the extracellular binding pocket of metabotropic group 1 receptors, which includes mGluR5 but not mGluR8 (61,65).…”

“…This indicates an occlusive action of DHPG and A␤o. One possible explanation is an overlapping binding site of A␤o-PrP C complexes and DHPG on mGluR5, the latter being located in the extracellular binding pocket (61,65). The effect could also be explained by DHPG-triggered conformational changes of mGluR5, which prevent A␤o-PrP C complexes from binding and inducing further conformational alterations.…”

Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors

“…Thus, for medicinal chemists to find the best therapeutic profile of mGlu 4 allosteric ligands, further experiments will be necessary to elucidate this point. The existence of multiple allosteric sites in the 7TM of mGluRs has been proposed, notably in mGlu 5 (12,52). For example, the 2 mGlu 5 PAMs, CPPHA and VU0357121, do not displace MPEP, contrary to other mGlu 5 PAMs such as VU29, for example (53,54).…”

Allosteric Binding Site and Activation Mechanism of Class C G-Protein Coupled Receptors: Metabotropic Glutamate Receptor Family

“…The group I mGluRs have been considered promising therapeutic targets to treat diseases including cancer, chronic pain, schizophrenia, Alzheimer's disease, and anxiety (4,5). Group II and III mGluRs, on the other hand, are mainly presynaptic, signal through the G i /G o protein signaling pathway, and decrease NMDA receptor activity and risk of excitotoxicity (3). All mGluRs form stable disulphide-linked dimers (3,12).…”

“…Group II and III mGluRs, on the other hand, are mainly presynaptic, signal through the G i /G o protein signaling pathway, and decrease NMDA receptor activity and risk of excitotoxicity (3). All mGluRs form stable disulphide-linked dimers (3,12). Each monomer contains an extracellular Venus Flytrap domain (VFTD, orthosteric glutamate binding site; 13), 7 trans-membrane domains (7TMD, contains the allosteric binding site), and a so-called cysteine-rich domain (CRD, bridged the VFTD and 7TMD; 14).…”