9MQH
Inactive Mu-Opioid Receptor with Nb6M, NabFab, and isoquinuclidine compound #33
Summary for 9MQH
| Entry DOI | 10.2210/pdb9mqh/pdb |
| EMDB information | 48524 |
| Descriptor | Mu-type opioid receptor (1 entity in total) |
| Functional Keywords | g-protein coupled receptor, mu-opioid, isoquinuclidine, antagonist, nanobodies, fabs, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 46081.36 |
| Authors | Kim, J.Y.,Vigneron, S.F.,Billesbolle, C.,Manglik, A.,Shoichet, B.K. (deposition date: 2025-01-03, release date: 2025-02-12) |
| Primary citation | Vigneron, S.F.,Ohno, S.,Braz, J.,Kim, J.Y.,Kweon, O.S.,Webb, C.,Billesbolle, C.,Bhardwaj, K.,Irwin, J.,Manglik, A.,Basbaum, A.I.,Ellman, J.A.,Shoichet, B.K. Docking 14 million virtual isoquinuclidines against the mu and kappa opioid receptors reveals dual antagonists-inverse agonists with reduced withdrawal effects. Biorxiv, 2025 Cited by PubMed Abstract: Large library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving many interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration and targeted docking of isoquinuclidines. These "natural-product-like" molecules are rare in the current libraries and are functionally congested, making them interesting as receptor probes. Using a modular, four-component reaction scheme, we built and docked a virtual library of over 14.6 million isoquinuclidines against both the μ- and -opioid receptors (MOR and KOR, respectively). Synthesis and experimental testing of 18 prioritized compounds found nine ligands with low μM affinities. Structure-based optimization revealed low- and sub-nM antagonists and inverse agonists targeting both receptors. Cryo-electron microscopy (cryoEM) structures illuminate the origins of activity on each target. In mouse behavioral studies, a potent member of the series with joint MOR-antagonist and KOR-inverse-agonist activity reversed morphine-induced analgesia, phenocopying the MOR-selective anti-overdose agent naloxone. Encouragingly, the new molecule induced less severe opioid-induced withdrawal symptoms compared to naloxone during withdrawal precipitation, and did not induce conditioned-place aversion, likely reflecting a reduction of dysphoria due to the compound's KOR-inverse agonism. The strengths and weaknesses of bespoke library docking, and of docking for opioid receptor polypharmacology, will be considered. PubMed: 39868130DOI: 10.1101/2025.01.09.632033 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.9 Å) |
Structure validation
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