Computational Identification of a Potential Novel Non-Classical μ-Opioid Receptor State-Dependent Inverse Agonist

The μ-opioid receptor (MOR) is a central mediator of analgesia and a key target for opioid therapeutics, with ligands capable of acting as agonists, antagonists, or inverse agonists depending on receptor state stabilization [1-4]. Here, we report an in silico docking analysis of a structurally novel polycyclic, non-classical opioid-like ligand across multiple MOR conformations and related opioid receptors. Docking results reveal preferential stabilization of the inactive MOR conformation (PDB: 9MQ1), including poses that form a salt-bridge interaction with Asp83 of the conserved DRY motif and extensive hydrophobic contacts with TM6 and TM7, consistent with inverse agonist-like stabilization of the inactive receptor state [1,2,5]. While higher docking scores were observed in active MOR conformations (5C1M), these poses lacked DRY motif engagement and did not exhibit interaction patterns associated with inverse agonism [3,4]. Moderate binding was observed at δ-and κ-opioid receptors, suggesting partial off-target affinity [5]. Ensemble-level analysis indicates statedependent modulation, where specific microswitch engagement, rather than absolute docking energy, governs functional bias, a recognized feature of GPCR inverse agonism [1,2,5]. Together, these findings identify a previously unreported non-morphinan scaffold with potential utility as a research probe for studying constitutive MOR activity and statedependent GPCR modulation.