title: The use of conformationally thermostabilised GPCRs in drug discovery: application to fragment, structure and biophysical techniques.
abstract: Recent developments in receptor stabilisation have facilitated major advances in G protein-coupled receptor (GPCR) research, notably structural biology, over the past eight years. Here we review the application of fragment, structure and biophysical techniques using stabilised GPCRs (StaR proteins), and their impact in the drug discovery process. These techniques have, most recently, been utilised in the discovery of the non-alkyne mGlu5negative allosteric modulator HTL14242, in addition to the dual orexin receptor antagonist HTL6641, with differentiated residence time kinetics.
authors.affiliation: Heptares Therapeutics, Biopark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom. Electronic address: ben.tehan@heptares.com.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Tehan
authors.affiliation: Heptares Therapeutics, Biopark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: Christopher
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology; D011487:Protein Conformation; D055550:Protein Stability; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5 / Q000187:drug effects / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism; D013696:Temperature
chemical_list: C000602649:3-chloro-5-(6-(5-fluoropyridin-2-yl)pyrimidin-4-yl)benzonitrile; D000068796:Orexin Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D064529:Receptor, Metabotropic Glutamate 5; D043562:Receptors, G-Protein-Coupled