title: Computational studies to predict or explain G protein coupled receptor polypharmacology.
abstract: Since G protein-coupled receptors (GPCRs) belong to a very large superfamily of evolutionarily related receptors (>800 members in humans), and due to the rapid progress on their structural biology, they are ideal candidates for polypharmacology studies. Broad screening and bioinformatics/chemoinformatics have been applied to understanding off-target effects of GPCR ligands. It is now feasible to approach the question of GPCR polypharmacology using molecular modeling and the available X-ray GPCR structures. As an example, large and sterically constrained adenosine derivatives (potent adenosine receptor ligands with low conformational freedom and multiple extended substituents) were screened for binding at diverse receptors. Unanticipated off-target interactions, including at biogenic amine receptors, were then modeled using a structure-based approach to provide a consistent understanding of recognition. A conserved Asp in TM3 changed its role from counterion for biogenic amines to characteristic H-bonding to adenosine. The same systematic approach could potentially be applied to many GPCRs or other receptors using other sets of congeneric ligands.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA. Electronic address: kennethj@helix.nih.gov.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.affiliation: Department of Chemistry and Center for Behavioral Neuroscience, American University, Washington, DC 20016, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
mesh_terms: D019295:Computational Biology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D064798:Polypharmacology; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism
chemical_list: D043562:Receptors, G-Protein-Coupled
keywords: G protein-coupled receptors; bioinformatics; chemoinformatics; molecular modeling