Abstract
The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.
Highlights
The μ opioid receptor (MOR), a member of the opioid neuromodulatory system and of the large family of G protein-coupled receptors (GPCRs), is the main pharmacological target for the management of moderate to severe pain, and is of therapeutic value for the treatment of drug abuse, alcohol abuse, and gastrointestinal motility dysfunction[1,2]
A plethora of different strategies and software solutions is nowadays available[11], and the current study applied pharmacophore models generated with LigandScout[12], shape-based models created with Rapid Overlay of Chemical Structures (ROCS)[13,14], and a docking workflow with GOLD15,16 for virtual screening of a commercial compound library towards discovery of novel agonists and antagonists at the MOR
One prominent hypothesis stated that the size of the substitution at the N17 position in morphinans (Fig. 1) was responsible for the different biological activity observed for MOR ligands as agonists and antagonists[5]
Summary
The μ opioid receptor (MOR), a member of the opioid neuromodulatory system and of the large family of G protein-coupled receptors (GPCRs), is the main pharmacological target for the management of moderate to severe pain, and is of therapeutic value for the treatment of drug abuse, alcohol abuse, and gastrointestinal motility dysfunction[1,2]. The MORs are integral membrane proteins widely distributed throughout the central nervous system and the periphery They are the molecular targets of a large variety of opioid drugs, of which morphinans represent one of the main classes of ligands binding to the MOR, as well as clinically useful agents[2,3,4]. One common hypothesis states that the size of the N-substituent in morphinans may determine their biological activity Larger substituents such as allyl- or cyclopropylmethyl- at the nitrogen are commonly associated with an antagonist property, whereas agonists mainly contain a methyl group[5,6]. In 2012, the first X-ray crystal structure of the MOR from murine origin was published in complex with the irreversible morphinan antagonist β -funaltrexamine (β -FNA) (PDB-entry 4DKL10), aiming to provide significant details on the ligand-receptor binding patterns at the molecular level. The identification of new scaffolds interacting with the MOR could have a major impact on the development of superior treatments of neurological and other human disorders, and the availability of pharmacological tools for the study of this receptor system
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