9MQL

Locally-Refined Inactive Kappa-Opioid Receptor with Nb6M, NabFab, and isoquinuclidine compound #020_E1

This is a non-PDB format compatible entry.

Summary for 9MQL

• Entry DOI: 10.2210/pdb9mql/pdb
• Related: 9MQK
• EMDB information: 48527 48528
• Descriptor: Kappa-Opioid Receptor, methyl (1S,3R,4S,6S,8M)-2-[(1-ethyl-1H-pyrazol-4-yl)methyl]-8-(3-hydroxyphenyl)-3,4-dimethyl-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate (2 entities in total)
• Functional Keywords: g-protein coupled receptor, kappa-opioid, isoquinuclidine, antagonist, nanobodies, fabs, membrane protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 1
• Total formula weight: 44022.40

Authors

Kim, J.Y.,Vigneron, S.F.,Billesbolle, C.,Manglik, A.,Shoichet, B.K. (deposition date: 2025-01-03, release date: 2025-02-12, Last modification date: 2025-03-12)

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

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: 39868130
DOI: 10.1101/2025.01.09.632033

Experimental method

ELECTRON MICROSCOPY (2.96 Å)