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 κ-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.
Keywords: g-protein coupled receptors(gpcr), endogenous ligands, extracellular loop (el), third transmembrane helix (tm3), opioid/nociceptin receptors, enkephalins, analgesia, mutagenesis, drosophila, cysteine
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