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Selective GPCR ligands
Bioorganic & Medicinal Chemistry 23 (2015) 3879
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc
Preface
Selective GPCR ligands Biologically active compounds exert their efficacy by interacting with specific targets including receptors, ion channels, transporters, enzymes or transcription factors. Medicinal chemistry and chemical biology aim to develop molecular probes to understand and control target–ligand interactions. 30% of drugs on the market exert their biological activities upon binding to G Protein-Coupled Receptors (GPCRs). GPCRs comprise a large superfamily of target proteins, whereby nearly 800 different human genes encode for GPCRs. As biological targets, GPCRs are associated with exceptional progress in the field of drug research, enabling the application of molecular strategies for the discovery of innovative therapeutic principles. Numerous severe diseases are associated with dysfunctions of GPCR regulation. The biological activity of a GPCR is attenuated by various stimuli, including photons, ions, hormones and neurotransmitters. Therefore, a classic strategy targeting GPCRs involves the development of synthetic agonists, which mimic the endogenous ligand and activate the receptor, or antagonists, which serve to prevent activation of the receptor. However, agonists and antagonists targeting GPCRs often demonstrate multidimensional selectivity profiles, resulting in both desired and adverse effects. Over the years, selectivity of GPCR ligands has evolved from receptor subtype selectivity, to now include selectivity of intracellular signaling pathway activation (termed functional selectivity or biased agonism), selectivity for receptor conformations, receptor dimers, allosteric sites, orthologues and mutants. Thus, optimization of ligand affinity and, more importantly selectivity, is key to successful development of new and improved GPCR-addressing pharmacological tools and potential drugs. Some modern methods for further understanding ligand–receptor interactions include the development of fluorescently or radioactively labelled molecular probes, which may be used for functional studies and imaging purposes, respectively. Moreover, covalent and slowly diffusing probes are necessary to elucidate the structure target–ligand complexes by X-ray crystallography, NMR and high resolution microscopy. Over the last few years, outstanding scientific results have placed the spotlight on the GPCR field. The expanding number of X-ray crystal structures of druggable GPCRs in complex with ligands have provided significantly enhanced insights into the molecular determinants responsible
http://dx.doi.org/10.1016/j.bmc.2015.03.030 0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.
for the selectivity of ligands towards distinct receptor subtype, mutants and orthologues. Moreover, the structure of different GPCR active states has promoted the identification of molecular interactions discriminating between inverse agonists, antagonists and agonists. These fundamental results stimulate the rational discovery of drugs able to stabilize particular conformational states, thus leading to greater selectivity of ligands. Other recent breakthroughs have demonstrated that there is growing evidence that homo- and heterodimers affect and diversify G-protein coupling. Furthermore, the concept of functional selectivity (biased signaling) owing to ligand-specific GPCR conformations has been corroborated. Taking advantage of these recent discoveries in a transdisciplinary field, the current Symposium in Print publishes 2 reviews and 17 articles on molecular investigations of ligand– GPCR interactions in order to further our understanding of the principles of ligand binding and selectivity. Moreover, a number of articles show a rational development of highly selective molecular probes. These excellent contributions also demonstrate that GPCR research has become very comprehensive, involving fragment based approaches, structure based design, mass spectrometrydetected bioavailability studies, click chemistry, bivalent ligands, PET-tracers and lead optimization. I would like to thank all authors of this issue for providing such an inspiring collection of research that demonstrates the relevance and progress of current bioorganic and medicinal chemistry in the field of GPCR ligands, as well as Prof. Herbert Waldmann for the invitation to serve as the Guest Editor, and Birgit Apprecht and Anne Stößel for their assistance with the preparation of the current Symposium in Print. Peter Gmeiner Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany E-mail address: [email protected] URL: http://www.medchem.fau.de Available online 14 March 2015
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc
Preface
Selective GPCR ligands Biologically active compounds exert their efficacy by interacting with specific targets including receptors, ion channels, transporters, enzymes or transcription factors. Medicinal chemistry and chemical biology aim to develop molecular probes to understand and control target–ligand interactions. 30% of drugs on the market exert their biological activities upon binding to G Protein-Coupled Receptors (GPCRs). GPCRs comprise a large superfamily of target proteins, whereby nearly 800 different human genes encode for GPCRs. As biological targets, GPCRs are associated with exceptional progress in the field of drug research, enabling the application of molecular strategies for the discovery of innovative therapeutic principles. Numerous severe diseases are associated with dysfunctions of GPCR regulation. The biological activity of a GPCR is attenuated by various stimuli, including photons, ions, hormones and neurotransmitters. Therefore, a classic strategy targeting GPCRs involves the development of synthetic agonists, which mimic the endogenous ligand and activate the receptor, or antagonists, which serve to prevent activation of the receptor. However, agonists and antagonists targeting GPCRs often demonstrate multidimensional selectivity profiles, resulting in both desired and adverse effects. Over the years, selectivity of GPCR ligands has evolved from receptor subtype selectivity, to now include selectivity of intracellular signaling pathway activation (termed functional selectivity or biased agonism), selectivity for receptor conformations, receptor dimers, allosteric sites, orthologues and mutants. Thus, optimization of ligand affinity and, more importantly selectivity, is key to successful development of new and improved GPCR-addressing pharmacological tools and potential drugs. Some modern methods for further understanding ligand–receptor interactions include the development of fluorescently or radioactively labelled molecular probes, which may be used for functional studies and imaging purposes, respectively. Moreover, covalent and slowly diffusing probes are necessary to elucidate the structure target–ligand complexes by X-ray crystallography, NMR and high resolution microscopy. Over the last few years, outstanding scientific results have placed the spotlight on the GPCR field. The expanding number of X-ray crystal structures of druggable GPCRs in complex with ligands have provided significantly enhanced insights into the molecular determinants responsible
http://dx.doi.org/10.1016/j.bmc.2015.03.030 0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.
for the selectivity of ligands towards distinct receptor subtype, mutants and orthologues. Moreover, the structure of different GPCR active states has promoted the identification of molecular interactions discriminating between inverse agonists, antagonists and agonists. These fundamental results stimulate the rational discovery of drugs able to stabilize particular conformational states, thus leading to greater selectivity of ligands. Other recent breakthroughs have demonstrated that there is growing evidence that homo- and heterodimers affect and diversify G-protein coupling. Furthermore, the concept of functional selectivity (biased signaling) owing to ligand-specific GPCR conformations has been corroborated. Taking advantage of these recent discoveries in a transdisciplinary field, the current Symposium in Print publishes 2 reviews and 17 articles on molecular investigations of ligand– GPCR interactions in order to further our understanding of the principles of ligand binding and selectivity. Moreover, a number of articles show a rational development of highly selective molecular probes. These excellent contributions also demonstrate that GPCR research has become very comprehensive, involving fragment based approaches, structure based design, mass spectrometrydetected bioavailability studies, click chemistry, bivalent ligands, PET-tracers and lead optimization. I would like to thank all authors of this issue for providing such an inspiring collection of research that demonstrates the relevance and progress of current bioorganic and medicinal chemistry in the field of GPCR ligands, as well as Prof. Herbert Waldmann for the invitation to serve as the Guest Editor, and Birgit Apprecht and Anne Stößel for their assistance with the preparation of the current Symposium in Print. Peter Gmeiner Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany E-mail address: [email protected] URL: http://www.medchem.fau.de Available online 14 March 2015