Structure-Based Discovery of Allosteric Modulators of Two Related Class B G-Protein-Coupled Receptors
| Autor: | Fabrizio Giordanetto, Didier Rognan, Chantal Rein, Chris de Graaf, David Piwnica |
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| Rok vydání: | 2011 |
| Předmět: |
Databases
Factual Molecular Sequence Data Allosteric regulation Drug Evaluation Preclinical Molecular Dynamics Simulation Ligands Receptors Corticotropin-Releasing Hormone Biochemistry Structure-Activity Relationship Allosteric Regulation Drug Discovery Receptors Glucagon Humans Structure–activity relationship Amino Acid Sequence General Pharmacology Toxicology and Pharmaceutics Binding site Receptor G protein-coupled receptor Pharmacology Virtual screening Binding Sites Chemistry fungi Organic Chemistry Combinatorial chemistry Protein Structure Tertiary Docking (molecular) Mutagenesis Site-Directed Molecular Medicine Sequence Alignment Glucagon receptor hormones hormone substitutes and hormone antagonists |
| Zdroj: | ChemMedChem. 6:2159-2169 |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201100317 |
| Popis: | Despite the availability of X-ray crystal structure data for several members of the G-protein-coupled receptor (GPCR) superfamily, structure-based discovery of GPCR ligands has been exclusively restricted to class A (rhodopsin-like) receptors. Herein we report the identification, by a docking-based virtual screening approach, of noncompetitive ligands for two related class B (secretin-like) GPCRs: the glucagon receptor (GLR) and the glucagon-like peptide 1 receptor (GLP-1R). Starting from a knowledge-based three-dimensional model of the GLR, a database of 1.9 million commercially available drug-like compounds was screened for chemical similarity to existing GLR noncompetitive antagonists and docked to the transmembrane cavity of the GLR; 23 compounds were then selected based on protein-ligand interaction fingerprints, and were then purchased and evaluated for in vitro binding to GLR and modulation of glucagon-induced cAMP release. Two of the 23 compounds inhibited the effect of glucagon in a dose-dependent manner, with one inhibitor exhibiting the same potency as L-168 049, a reference noncompetitive GLR antagonist, in a whole-cell-based functional assay. Interestingly, one virtual hit that was inactive at the GLR was shown to bind to GLP-1R and potentiate the response to the endogenous GLP-1 ligand. |
| Databáze: | OpenAIRE |
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