title: Modeling G protein-coupled receptors in complex with biased agonists.
abstract: The biological response to the activation of G protein-coupled receptors (GPCRs) typically originates from the simultaneous modulation of various signaling pathways that lead to distinct biological consequences. Hence, 'biased agonists' (i.e., compounds that selectively activate one of the pathways while blocking the others) are highly sought-after molecules to provide fine-tuned pharmacological interventions. This review describes strategies that can be deployed to model the conformation of GPCRs in complex with ligands endowed with specific signaling profiles useful for the generation of hypotheses on the structural requirements for the activation of different signaling pathways or for rational computer-aided ligand discovery campaigns. In particular, it focuses on strategies potentially applicable to model the global or local conformational states of GPCRs stabilized by specific ligands.
authors.affiliation: Department of Chemistry, American University, Washington, DC 20016, USA; Center for Behavioral Neuroscience, American University, Washington, DC 20016, USA. Electronic address: costanzi@american.edu.
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled
keywords: flexible docking; global conformational changes; local conformational changes; molecular dynamics; normal mode analysis; virtual screening