title: The function of the extracellular regions in opioid receptor binding: insights from computational biology.
abstract: Pain management using opioid analgesics strives to achieve three goals: maximum efficacy, minimal risk of tolerance and physical dependence, and negligible side effects. Following the cloning of opioid and nociceptin receptors, novel ligands can be designed to target specific residues of these membrane proteins with the goal of improving efficacy and reducing side effects through selectivity. For the most part, ligand design has focused on binding sites located in the transmembrane region of the receptors, and has ignored the extracellular domains. In this review, we discuss the evidence for the interaction of the extracellular regions with opioids and show how computational biology tools can be used to model these domains for use in drug discovery. A computational model of the kappa-opioid receptor which includes the loop regions is presented. The model combines knowledge-based information, bioinformatics and computational tools to identify regions of the extracellular loop domains that can be targeted by drug design.
authors.affiliation: Certusoft, Inc. 7900 West 78th Street, Suite 165, Minneapolis, MN 55439, USA. germana@certusoft.com
authors.forename: M Germana
authors.initials: MG
authors.lastname: Paterlini
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D001665:Binding Sites; D003001:Cloning, Molecular; D019295:Computational Biology; D005110:Extracellular Space / Q000378:metabolism*; D008024:Ligands; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010146:Pain / Q000188:drug therapy / Q000517:prevention & control; D011957:Receptors, Opioid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000094942:Nociceptin Receptor
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D000094942:Nociceptin Receptor