Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Docking 14 million virtual isoquinuclidines against the mu and kappa opioid receptors reveals dual antagonists-inverse agonists with reduced withdrawal effects.
Journal, issue, pages	bioRxiv, Year 2025
Publish date	Jan 14, 2025
Authors	Seth F Vigneron / Shohei Ohno / Joao Braz / Joseph Y Kim / Oh Sang Kweon / Chase Webb / Christian Billesbølle / Karnika Bhardwaj / John Irwin / Aashish Manglik / Allan I Basbaum / Jonathan A Ellman / Brian K Shoichet /
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 ...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.
External links	bioRxiv / PubMed:39868130 / PubMed Central
Methods	EM (single particle)
Resolution	2.96 - 3.9 Å
Structure data	48524 9mqh EMDB-48524, PDB-9mqh: Inactive Mu-Opioid Receptor with Nb6M, NabFab, and isoquinuclidine compound #33 Method: EM (single particle) / Resolution: 3.9 Å 48525 9mqi EMDB-48525: Inactive Mu-Opioid Receptor with Nb6M, NabFab, and isoquinuclidine compound#020_E1 PDB-9mqi: Inactive Mu-Opioid Receptor with Nb6M, NabFab, and isoquinuclidine compound #020_E1 Method: EM (single particle) / Resolution: 3.3 Å 48526 9mqj EMDB-48526, PDB-9mqj: Locally-refined Inactive Mu-Opioid Receptor with Nb6M, NabFab, and isoquinuclidine compound #020_E1 Method: EM (single particle) / Resolution: 3.23 Å 48527 9mqk EMDB-48527, PDB-9mqk: Inactive Kappa-Opioid Receptor with Nb6M, NabFab, and isoquinuclidine compound #020_E1 Method: EM (single particle) / Resolution: 3.18 Å 48528 9mql EMDB-48528, PDB-9mql: Locally-Refined Inactive Kappa-Opioid Receptor with Nb6M, NabFab, and isoquinuclidine compound #020_E1 Method: EM (single particle) / Resolution: 2.96 Å
Chemicals	PDB-1bnm: CARBONIC ANHYDRASE II INHIBITOR
Source	homo sapiens (human) synthetic construct (others) mus musculus (house mouse)
Keywords	MEMBRANE PROTEIN / G-protein coupled receptor / Mu-opioid / isoquinuclidine / antagonist / nanobodies / fabs / Kappa-opioid