The kappa opioid receptor modulators have gained great interest for their potentiality to counteract substance abuse as well as manage several CNS disorders including depression. Despite the great efforts, very few successful agents have emerged out of the pipeline and into the market. With a glaze of hope, a novel class of pure/selective opioid receptor modulator was introduced based on the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, non-morphinan chemical scaffold. Among this class, two drugs have emerged including the peripheral kappa receptor antagonist; JDTic, and the FDA-approved Mu opioid receptor antagonist; Alvimopan. Although both drugs exhibit great opioid receptor subtype selectivity profiles, the molecular basis for such selectivity is still vague and require further investigation. Here, we present an <i>in-silico</i> investigation for the differential binding and affinity of these selective agentstowards the kappa opioid receptor subtype through molecular docking, coupled with long-time molecular dynamics simulations. The molecular bases of compound’s selectivity were illustrated to be highly correlated with the ligand/targetcombined polar and hydrophobic interactions with the selectivity pocket residues; Val108, Thr111, and Val118, as well as their vicinal residues Asp138 and Trp287. Moreover, our results also demonstrate, for the first time, that the message-address model could be adopted by these non-morphinan ligands for both KOP efficacy and selectivity through relevant contacts with Glu297 residue.

Insights into the selectivity of small molecule inhibitors against the kappa opioid receptor: A comparative computational investigation

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.