Leveraging allostery to improve G protein-coupled receptor (GPCR)-directed therapeutics: cannabinoid receptor 1 as discovery target

摘要: ABSTRACTIntroduction: Allosteric modulators of G-protein coupled receptors (GPCRs) hold the promise improved pharmacology and safety over typical orthosteric GPCR ligands. These features are particularly relevant to cannabinoid receptor 1 (CB1R) GPCR, since CB1R ligands associated with adverse events that limit their translational potential.Areas covered: The contextual basis for applying allostery is considered from pharmacological, drug-discovery, medicinal standpoints. Rational design small-molecule allosteric as potential pharmacotherapeutics would be greatly facilitated by direct experimental characterization structure-function correlates underlying biological activity chemically-diverse modulators, ligand-binding binding pockets, amino acid contact residues critical ligand engagement activity. In these regards, designer covalent probes exhibiting well-characterized molecular ...