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Fitting the complexity of GPCRs modulation into simple hypotheses of ligand design.

ABSTRACT: G-protein coupled receptors (GPCR(s)) are a large family of membrane-bound receptors that mediate a wide range of physiologic responses to hormones, neurotransmitters and dietary lipids, which represent an important class of drug targets. Significant chemical space regions have been explored both in the academia and by pharmaceutical companies, in the quest for new GPCR modulators as potential therapeutic agents. This accumulated body of evidence provides new opportunities to evaluate potential features of GPCR agonists and antagonists, and how to distinguish them. In this study, the chemical space covered within the WOMBAT database by GPCRs modulators was investigated with the aim of identifying specific molecular determinants that distinguish GPCR agonists from antagonists. While instrumental to get insights into the design strategies of GPCRs modulators, the results of this study provide novel clues on the molecular mechanisms that underlie the complexity of GPCR modulation.

SUBMITTER: Custodi C

PROVIDER: S-EPMC3508176 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Fitting the complexity of GPCRs modulation into simple hypotheses of ligand design.

Custodi Chiara C Nuti Roberto R Oprea Tudor I TI Macchiarulo Antonio A

Journal of molecular graphics & modelling 20120720

G-protein coupled receptors (GPCR(s)) are a large family of membrane-bound receptors that mediate a wide range of physiologic responses to hormones, neurotransmitters and dietary lipids, which represent an important class of drug targets. Significant chemical space regions have been explored both in the academia and by pharmaceutical companies, in the quest for new GPCR modulators as potential therapeutic agents. This accumulated body of evidence provides new opportunities to evaluate potential ...[more]

PMID: 23079642

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Project description:BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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 combining detailed analysis of crystallized or predicted protein-ligand binding modes, receptor mutation studies, and ligand structure-selectivity relationships that identify local differences in essential pharmacophore features in the ligand binding sites of different receptors. CONCLUSIONS AND IMPLICATIONS: We have performed structural chemogenomics studies that identify links between (hist)aminergic receptor ligands and their binding sites and binding modes. This knowledge can be used to identify structure-selectivity relationships that increase our understanding of ligand binding to (hist)aminergic receptors and hence can be used in future GPCR ligand discovery and design.

Dataset Information

Fitting the complexity of GPCRs modulation into simple hypotheses of ligand design.

Publications

Fitting the complexity of GPCRs modulation into simple hypotheses of ligand design.

Similar Datasets

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