Structural Insights into Notum Covalent Inhibition
By Yuguang Zhao, Fredrik Svensson, D. Steadman, S. Frew, A. Monaghan, M. Bictash, T. Moreira, R. Chalk, Weixian Lu, Paul V. Fish and 1 more. 2021
14 citations recorded by the source corpus.
The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Integrated(Wnt) ligands and deactivates Wnt signaling. Notum inhibitors can restore Wnt signaling which may be of therapeutic benefit for pathologies such as osteoporosis and Alzheimer’s disease. We report the identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters. High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduct formed between the nucleophile serine-232 and hydrolyzed butyric esters. The covalent interaction in solution was confirmed by mass spectrometry analysis. Inhibitory potencies vary depending on the warheads used. Mechanistically, the resulting acyl-enzyme intermediate carbonyl atom is positioned at an unfavorable angle for the approach of the active site water, which, combined with strong hydrophobic interactions with the enzyme pocket residues, hinders the intermediate from being further processed and results in covalent inhibition. These insights into Notum catalytic inhibition may guide development of more potent Notum inhibitors.
Subfields: Computational Theory and Mathematics, Pharmacology
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- C. Patel
Citations in the corpus
- Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity (2023, methodology): “The first round of design was guided by the X-ray crystal structure of Notum-2b (PDB: 7B37) that indicated a disordered state of the pendant butyric chain, likely due to a steric clash with Ser232 [22].”