title: GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1-2 September 2014.
abstract: G-protein coupled receptors (GPCRs) are the targets of over half of all prescribed drugs today. The UniProt database has records for about 800 proteins classified as GPCRs, but drugs have only been developed against 50 of these. Thus, there is huge potential in terms of the number of targets for new therapies to be designed. Several breakthroughs in GPCRs biased pharmacology, structural biology, modelling and scoring have resulted in a resurgence of interest in GPCRs as drug targets. Therefore, an international conference, sponsored by the Royal Society, with world-renowned researchers from industry and academia was recently held to discuss recent progress and highlight key areas of future research needed to accelerate GPCR drug discovery. Several key points emerged. Firstly, structures for all three major classes of GPCRs have now been solved and there is increasing coverage across the GPCR phylogenetic tree. This is likely to be substantially enhanced with data from x-ray free electron sources as they move beyond proof of concept. Secondly, the concept of biased signalling or functional selectivity is likely to be prevalent in many GPCRs, and this presents exciting new opportunities for selectivity and the control of side effects, especially when combined with increasing data regarding allosteric modulation. Thirdly, there will almost certainly be some GPCRs that will remain difficult targets because they exhibit complex ligand dependencies and have many metastable states rendering them difficult to resolve by crystallographic methods. Subtle effects within the packing of the transmembrane helices are likely to mask and contribute to this aspect, which may play a role in species dependent behaviour. This is particularly important because it has ramifications for how we interpret pre-clinical data. In summary, collaborative efforts between industry and academia have delivered significant progress in terms of structure and understanding of GPCRs and will be essential for resolving problems associated with the more difficult targets in the future.
authors.affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK, Alexander.Heifetz@Evotec.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.forename: Gebhard F X
authors.initials: GF
authors.lastname: Schertler
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Tate
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.forename: Vsevolod V
authors.initials: VV
authors.lastname: Gurevich
authors.forename: Daniel
authors.initials: D
authors.lastname: Fourmy
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Marshall
authors.forename: R Ian
authors.initials: RI
authors.lastname: Storer
authors.forename: Isabel
authors.initials: I
authors.lastname: Moraes
authors.forename: Irina G
authors.initials: IG
authors.lastname: Tikhonova
authors.forename: Christofer S
authors.initials: CS
authors.lastname: Tautermann
authors.forename: Peter
authors.initials: P
authors.lastname: Hunt
authors.forename: Tom
authors.initials: T
authors.lastname: Ceska
authors.forename: Simon
authors.initials: S
authors.lastname: Hodgson
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Bodkin
authors.forename: Shweta
authors.initials: S
authors.lastname: Singh
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Law
authors.forename: Philip C
authors.initials: PC
authors.lastname: Biggin
mesh_terms: D000818:Animals; D003198:Computer Simulation; D003299:Cooperative Behavior; D003461:Crystallography; D055808:Drug Discovery; D004345:Drug Industry; D006801:Humans; D008958:Models, Molecular; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014495:Universities
chemical_list: D043562:Receptors, G-Protein-Coupled