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

摘要: Background and Purpose Chemogenomics focuses on the discovery of new connections between chemical biological space leading to protein targets biologically active molecules. G-protein coupled receptors (GPCRs) are a particularly interesting family for chemogenomics studies because there is an overwhelming amount ligand binding affinity data available. The increasing number aminergic GPCR crystal structures now first time allows integration with high-resolution structural analyses GPCR-ligand complexes. Experimental Approach In this study, we have combined data, receptor mutagenesis studies, amino acid sequence (hist)aminergic interactions. This integrated analysis used more accurately describe molecular determinants selectivity in different key regions crystallized GPCRs, histamine particular. Key Results Our investigations highlight correlations differences similarity site receptors. Apparent discrepancies can be explained by combining detailed or predicted protein-ligand modes, mutation structure-selectivity relationships that identify local essential pharmacophore features sites receptors. Conclusions Implications We performed links ligands their modes. knowledge increase our understanding hence future design. Linked Articles This article part themed issue Histamine Pharmacology Update. To view other articles visit http://dx.doi.org/ 10.1111/bph.2013.170.issue-1