7TM X-ray structures for class C GPCRs as new drug-discovery tools. 1. mGluR5. Issue 2 (15th January 2016)

• Record Type: Journal Article
• Authors: Topiol, Sid; Sabio, Michael
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 2(2016)
• Page Start: 484
• Page End: 494
• Publication Date: 2016-01-15
• Subjects: Structure-based drug design -- Computer-aided drug discovery -- Metabotropic glutamate receptors (mGluRs) -- Mavoglurant -- Docking -- X-ray structure -- Negative allosteric modulators (NAMs) -- Positive allosteric modulators (PAMs); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.11.087
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We illustrate, with a focus on mGluR5, how the recently published, first X-ray structures of mGluR 7TM domains, specifically those of mGluR1 and mGluR5 complexed with negative allosteric modulators (NAMs), will begin to influence ligand- (e.g., drug- or sweetener-) discovery efforts involving class C GPCRs. With an extensive docking study allowing full ligand flexibility and full side chain flexibility of all residues in the ligand-binding cavity, we have predicted and analyzed the binding modes of a variety of structurally diverse mGluR5 NAM ligands, showing how the X-ray structures serve to effectively rationalize each ligand's binding characteristics. We demonstrated that the features that are inherent in our earlier overlay model are preserved in the protein structure-based docking models. We identified structurally diverse compounds, which potentially act as mGluR NAMs, and revealed binding-site differences by performing high-throughput docking using a database of approximately six million structures of commercially available compounds and the mGluR1 and mGluR5 X-ray structures. By comparing the 7TM domains of the mGluR5 and mGluR1 X-rays structures, we identified selectivity factors within group I of the mGluRs. Similarly, using homology models that we built for mGluR2 and mGluR4, we have identified the factors leading to the selectivity between group I and groups II and III for ligands occupying the deepest portion of the mGluR5 binding cavity. Finally, we have proposed a structure-based explanation of the pharmacological switching within a set of positive allosteric modulators (PAMs) and their corresponding, very close NAM analogs.