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Structural Insights into Notum Covalent Inhibition.

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Zhao Y, Svensson F, Steadman D, Frew S, Monaghan A, Bictash M, Moreira T, Chalk R, Lu W, Fish PV, Jones EY
OpenAccess logo J Med Chem 64 11354-11363 (2021)
Related entries: 7arg, 7b2v, 7b2y, 7b2z, 7b3f

Cited: 7 times
EuropePMC logo PMID: 34292747

Abstract

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.

Articles - 7b37 mentioned but not cited (3)

  1. Structural Insights into Notum Covalent Inhibition. Zhao Y, Svensson F, Steadman D, Frew S, Monaghan A, Bictash M, Moreira T, Chalk R, Lu W, Fish PV, Jones EY. J Med Chem 64 11354-11363 (2021)
  2. Computational Analysis of the Inhibition Mechanism of NOTUM by the ONIOM Method. Yildiz I, Yildiz BS. ACS Omega 7 13333-13342 (2022)
  3. Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity. Atkinson BN, Willis NJ, Zhao Y, Patel C, Frew S, Costelloe K, Magno L, Svensson F, Jones EY, Fish PV. Eur J Med Chem 251 115132 (2023)


Articles citing this publication (4)

  1. Proteome-Wide Profiling of the Covalent-Druggable Cysteines with a Structure-Based Deep Graph Learning Network. Du H, Jiang D, Gao J, Zhang X, Jiang L, Zeng Y, Wu Z, Shen C, Xu L, Cao D, Hou T, Pan P. Research (Wash D C) 2022 9873564 (2022)
  2. Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit. Willis NJ, Mahy W, Sipthorp J, Zhao Y, Woodward HL, Atkinson BN, Bayle ED, Svensson F, Frew S, Jeganathan F, Monaghan A, Benvegnù S, Jolly S, Vecchia L, Ruza RR, Kjær S, Howell S, Snijders AP, Bictash M, Salinas PC, Vincent JP, Jones EY, Whiting P, Fish PV. J Med Chem 65 7212-7230 (2022)
  3. HyperCys: A Structure- and Sequence-Based Predictor of Hyper-Reactive Druggable Cysteines. Gao M, Günther S. Int J Mol Sci 24 5960 (2023)
  4. Structural Analysis and Development of Notum Fragment Screening Hits. Zhao Y, Mahy W, Willis NJ, Woodward HL, Steadman D, Bayle ED, Atkinson BN, Sipthorp J, Vecchia L, Ruza RR, Harlos K, Jeganathan F, Constantinou S, Costa A, Kjær S, Bictash M, Salinas PC, Whiting P, Vincent JP, Fish PV, Jones EY. ACS Chem Neurosci 13 2060-2077 (2022)


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