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Front Pharmacol. 2014 Nov 28;5:255. doi: 10.3389/fphar.2014.00255. eCollection 2014.

Discovery of GPCR ligands for probing signal transduction pathways.

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European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena Siena, Italy ; Department of Biotechnology, Chemistry and Pharmacy, University of Siena Siena, Italy.
Department of Biotechnology, Chemistry and Pharmacy, University of Siena Siena, Italy.
Therapeutic Innovation Laboratory, UMR7200, CNRS/University of Strasbourg Illkirch, France.
Receptor Signaling and Therapeutic Innovations, GPCR and Cardiovascular and Metabolic Regulations, Biotechnology and Cell Signaling Laboratory, UMR 7242, CNRS/University of Strasbourg - LabEx Medalis Illkirch, France.


G protein-coupled receptors (GPCRs) are seven integral transmembrane proteins that are the primary targets of almost 30% of approved drugs and continue to represent a major focus of pharmaceutical research. All of GPCR targeted medicines were discovered by classical medicinal chemistry approaches. After the first GPCR crystal structures were determined, the docking screens using these structures lead to discovery of more novel and potent ligands. There are over 360 pharmaceutically relevant GPCRs in the human genome and to date about only 30 of structures have been determined. For these reasons, computational techniques such as homology modeling and molecular dynamics simulations have proven their usefulness to explore the structure and function of GPCRs. Furthermore, structure-based drug design and in silico screening (High Throughput Docking) are still the most common computational procedures in GPCRs drug discovery. Moreover, ligand-based methods such as three-dimensional quantitative structure-selectivity relationships, are the ideal molecular modeling approaches to rationalize the activity of tested GPCR ligands and identify novel GPCR ligands. In this review, we discuss the most recent advances for the computational approaches to effectively guide selectivity and affinity of ligands. We also describe novel approaches in medicinal chemistry, such as the development of biased agonists, allosteric modulators, and bivalent ligands for class A GPCRs. Furthermore, we highlight some knockout mice models in discovering biased signaling selectivity.


G protein-coupled receptors; GPCR; allosteric modulators; biased agonists; biased signaling; bivalent ligands; high throughput docking; homology modeling

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