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GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1-2 September 2014.

Heifetz A, Schertler GF, Seifert R, Tate CG, Sexton PM, Gurevich VV, Fourmy D, Cherezov V, Marshall FH, Storer RI, Moraes I, Tikhonova IG, Tautermann CS, Hunt P, Ceska T, Hodgson S, Bodkin MJ, Singh S, Law RJ, Biggin PC - Naunyn Schmiedebergs Arch. Pharmacol. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK, Alexander.Heifetz@Evotec.com.

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.

No MeSH data available.


Structure-based computational protocol for selective polypharmacology—figure adapted from a recent publication (Selvam et al. 2013)
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Fig11: Structure-based computational protocol for selective polypharmacology—figure adapted from a recent publication (Selvam et al. 2013)

Mentions: The recently released crystal structures of several bioamine receptors in complex with orthosteric and allosteric ligands enable the selectivity issue of antipsychotic drugs to be addressed at the molecular level. Thus, ‘structural snapshots’ provided by crystallography can be used to explore receptor motions using computer simulations. It is conceivable that allosteric and bitopic modulators interact with binding pockets that exist only in a subset of the receptor conformational space. Computer modelling can contribute to their identification by providing detailed insights into motions and interactions in the entire protein family and subsequently unravelling complex relationships in generated data within a reasonable time and at low cost. In academia, this approach has been undertaken with some promising results. For example, in the Tikhonova group, a computational protocol combining concepts from statistical mechanics and chemoinformatics have been developed to explore the flexibility of the bioamine receptors and identify geometrical and physicochemical properties that characterised the conformational space of the bioamine receptor family (Selvam et al. 2013). Figure 11 illustrates the molecular modelling steps undertaken to identify the unique pharmacophoric features of disease-active receptors.Fig. 11


GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1-2 September 2014.

Heifetz A, Schertler GF, Seifert R, Tate CG, Sexton PM, Gurevich VV, Fourmy D, Cherezov V, Marshall FH, Storer RI, Moraes I, Tikhonova IG, Tautermann CS, Hunt P, Ceska T, Hodgson S, Bodkin MJ, Singh S, Law RJ, Biggin PC - Naunyn Schmiedebergs Arch. Pharmacol. (2015)

Structure-based computational protocol for selective polypharmacology—figure adapted from a recent publication (Selvam et al. 2013)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4495723&req=5

Fig11: Structure-based computational protocol for selective polypharmacology—figure adapted from a recent publication (Selvam et al. 2013)
Mentions: The recently released crystal structures of several bioamine receptors in complex with orthosteric and allosteric ligands enable the selectivity issue of antipsychotic drugs to be addressed at the molecular level. Thus, ‘structural snapshots’ provided by crystallography can be used to explore receptor motions using computer simulations. It is conceivable that allosteric and bitopic modulators interact with binding pockets that exist only in a subset of the receptor conformational space. Computer modelling can contribute to their identification by providing detailed insights into motions and interactions in the entire protein family and subsequently unravelling complex relationships in generated data within a reasonable time and at low cost. In academia, this approach has been undertaken with some promising results. For example, in the Tikhonova group, a computational protocol combining concepts from statistical mechanics and chemoinformatics have been developed to explore the flexibility of the bioamine receptors and identify geometrical and physicochemical properties that characterised the conformational space of the bioamine receptor family (Selvam et al. 2013). Figure 11 illustrates the molecular modelling steps undertaken to identify the unique pharmacophoric features of disease-active receptors.Fig. 11

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK, Alexander.Heifetz@Evotec.com.

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.

No MeSH data available.