9MQL

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

これはPDB形式変換不可エントリーです。

9MQL の概要

• エントリーDOI: 10.2210/pdb9mql/pdb
• 関連するPDBエントリー: 9MQK
• EMDBエントリー: 48527 48528
• 分子名称: 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)
• 機能のキーワード: g-protein coupled receptor, kappa-opioid, isoquinuclidine, antagonist, nanobodies, fabs, membrane protein
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44022.40

構造登録者

Kim, J.Y.,Vigneron, S.F.,Billesbolle, C.,Manglik, A.,Shoichet, B.K. (登録日: 2025-01-03, 公開日: 2025-02-12, 最終更新日: 2025-03-12)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (2.96 Å)