A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design

British Journal of Pharmacology
Albert J KooistraChris de Graaf

Abstract

Chemogenomics focuses on the discovery of new connections between chemical and biological space leading to the discovery of new protein targets and biologically active molecules. G-protein coupled receptors (GPCRs) are a particularly interesting protein family for chemogenomics studies because there is an overwhelming amount of ligand binding affinity data available. The increasing number of aminergic GPCR crystal structures now for the first time allows the integration of chemogenomics studies with high-resolution structural analyses of GPCR-ligand complexes. In this study, we have combined ligand affinity data, receptor mutagenesis studies, and amino acid sequence analyses to high-resolution structural analyses of (hist)aminergic GPCR-ligand interactions. This integrated structural chemogenomics analysis is used to more accurately describe the molecular and structural determinants of ligand affinity and selectivity in different key binding regions of the crystallized aminergic GPCRs, and histamine receptors in particular. Our investigations highlight interesting correlations and differences between ligand similarity and ligand binding site similarity of different aminergic receptors. Apparent discrepancies can be explained by...Continue Reading

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Citations

Dec 18, 2013·Journal of Chemical Information and Modeling·Anat LevitMasha Y Niv
Aug 12, 2014·Neurochemical Research·Albert J KooistraHenk Timmerman
Aug 16, 2013·British Journal of Pharmacology·Paul L Chazot
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Jan 27, 2017·Journal of Chemical Information and Modeling·Ross McGuireChris de Graaf
Jun 25, 2016·Scientific Reports·Albert J KooistraChris de Graaf
Jan 18, 2018·ChemMedChem·Albert J KooistraChris de Graaf
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Oct 24, 2018·Journal of Medicinal Chemistry·Márton VassChris de Graaf
Jul 21, 2020·Journal of Chemical Information and Modeling·Enade P IstyastonoSudi Mungkasi

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