Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity.
By D. Steadman, Benjamin N. Atkinson, Yuguang Zhao, N. Willis, S. Frew, A. Monaghan, Chandni Patel, E. Armstrong, K. Costelloe, L. Magno and 4 more. 2021
11 citations recorded by the source corpus.
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.
Subfields: Computational Theory and Mathematics, Molecular Biology, Pharmacology
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Molecular Biology
Citations in the corpus
- Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity (2023, methodology): “Methods have been described in detail [21,22].”