Steadman, D;
Atkinson, BN;
Zhao, Y;
Willis, NJ;
Frew, S;
Monaghan, A;
Patel, C;
... Svensson, F; + view all
(2021)
Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity.
Journal of Medicinal Chemistry
, 65
(1)
pp. 562-578.
10.1021/acs.jmedchem.1c01735.
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Abstract
Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC50 < 500 nM. A critical selection process was then applied with two clusters and two singletons (1–4d) selected for hit validation. Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/β-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures.
| Type: | Article |
|---|---|
| Title: | Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acs.jmedchem.1c01735 |
| Publisher version: | https://doi.org/10.1021/acs.jmedchem.1c01735 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, INTERFERENCE COMPOUNDS PAINS, ACCURATE DOCKING, ENZYME NOTUM, DRUG, DISCOVERY, LIBRARIES, GLIDE, SET |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10141932 |
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