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.

GPCRs Revisited: New Insights Lead to Novel Drugs

“…However, a large number of GPCRs have large endogenous ligands and those molecules do not easily fit into a hydrophobic binding pocket first described for β-adrenoceptor. In fact, it has been shown that for peptide receptors, such as the opioid receptors, the endogenous ligands, including enkephalins, endorphins and dynorphins appear to primarily bind to orthosteric domains in the extracellular loops of the receptors [46-49]. For example, dynorphin A, the endogenous ligand for the kappa opioid receptor has been shown by mutagenesis studies, NMR analysis and molecular modeling to bind to the second extracellular loop of the kappa receptor [49-54].…”

Computational Methods in Drug Design: Modeling G Protein-Coupled Receptor Monomers, Dimers, and Oligomers

“…For example, for the -opioid receptor, there is evidence that extracellular loop regions form part of the binding site for ligands. 53 Loop conformations can be generated using homology modeling, database searching, or ab initio computational methods. A comprehensive review of the loop modeling literature is beyond the scope of this article.…”

Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic Benefits

“…The three main opioid receptors (μ, δ, κ) 14 show a high degree of sequence homology, and a common opioid receptor binding pocket within a helical transmembrane core. 15,16 The main differences in sequence between the receptors occur in the extracellular domains which contributes to ligand selectivity. 17 The opioid peptides reduce intracellular cAMP by inhibiting adenylate cyclase.…”