title: From G Protein-coupled Receptor Structure Resolution to Rational Drug Design.
abstract: A number of recent technical solutions have led to significant advances in G protein-coupled receptor (GPCR) structural biology. Apart from a detailed mechanistic view of receptor activation, the new structures have revealed novel ligand binding sites. Together, these insights provide avenues for rational drug design to modulate the activities of these important drug targets. The application of structural data to GPCR drug discovery ushers in an exciting era with the potential to improve existing drugs and discover new ones. In this review, we focus on technical solutions that have accelerated GPCR crystallography as well as some of the salient findings from structures that are relevant to drug discovery. Finally, we outline some of the approaches used in GPCR structure based drug design.
authors.affiliation: From Heptares Therapeutics Limited, BioPark, Broadwater Road, Welwyn Garden City AL7 3AX, United Kingdom ali.jazayeri@heptares.com.
authors.forename: Ali
authors.initials: A
authors.lastname: Jazayeri
authors.affiliation: From Heptares Therapeutics Limited, BioPark, Broadwater Road, Welwyn Garden City AL7 3AX, United Kingdom.
authors.forename: Joao M
authors.initials: JM
authors.lastname: Dias
authors.affiliation: From Heptares Therapeutics Limited, BioPark, Broadwater Road, Welwyn Garden City AL7 3AX, United Kingdom.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Marshall
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site / Q000187:drug effects; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries
keywords: G protein-coupled receptor (GPCR); X-ray crystallography; drug design; drug discovery; membrane protein