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G Protein-Coupled Receptor Transmembrane Binding Pockets and their Applications in GPCR Research and Drug Discovery: A Survey

[ Vol. 11 , Issue. 15 ]


Nicole A. Kratochwil, Silvia Gatti-McArthur, Marius C. Hoener, Lothar Lindemann, Andreas D. Christ, Luke G. Green, Wolfgang Guba, Rainer E. Martin, Pari Malherbe, Richard H. P. Porter, Jay P. Slack, Marcel Winnig, Henrietta Dehmlow, Uwe Grether, Cornelia Hertel, Robert Narquizian, Constantinos G. Panousis, Sabine Kolczewski and Lucinda Steward   Pages 1902 - 1924 ( 23 )


G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Hence, an automated method was developed that allows a fast analysis and comparison of these generic ligand binding pockets across the entire GPCR family by providing the relevant information for all GPCRs in the same format. This methodology compiles amino acids lining the TM binding pocket including parts of the ECL2 loop in a so-called 1D ligand binding pocket vector and translates these 1D vectors in a second step into 3D receptor pharmacophore models. It aims to support various aspects of GPCR drug discovery in the pharmaceutical industry. Applications of pharmacophore similarity analysis of these 1D LPVs include definition of receptor subfamilies, prediction of species differences within subfamilies in regard to in vitro pharmacology and identification of nearest neighbors for GPCRs of interest to generate starting points for GPCR lead identification programs. These aspects of GPCR research are exemplified in the field of melanopsins, trace amine-associated receptors and somatostatin receptor subtype 5. In addition, it is demonstrated how 3D pharmacophore models of the LPVs can support the prediction of amino acids involved in ligand recognition, the understanding of mutational data in a 3D context and the elucidation of binding modes for GPCR ligands and their evaluation. Furthermore, guidance through 3D receptor pharmacophore modeling for the synthesis of subtype-specific GPCR ligands will be reported. Illustrative examples are taken from the GPCR family class C, metabotropic glutamate receptors 1 and 5 and sweet taste receptors, and from the GPCR class A, e.g. nicotinic acid and 5-hydroxytryptamine 5A receptor.


Chemogenomics, GPCR, ligand binding pocket, 5-hydroxytryptamine receptors, melanopsins, metabotropic glutamate receptors, nicotinic acid family receptors, pharmacophore modeling, somatostatin receptors, sweet taste receptor, trace amine-associated receptors, 1D vectors, pharmacophore similarity analysis of


F. Hoffmann-La Roche Ltd., Pharma Research and Early Development, Bldg. 70/ 126, CH-4070 Basel, Switzerland.

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