7BD2

Notum Fragment 810

Summary for 7BD2

• Entry DOI: 10.2210/pdb7bd2/pdb
• Related: 7B84
• Descriptor: Palmitoleoyl-protein carboxylesterase NOTUM, SULFATE ION, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: notum inhibitor fragment screen, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 44446.00

Authors

Zhao, Y.,Jones, E.Y. (deposition date: 2020-12-21, release date: 2022-01-12, Last modification date: 2024-10-23)

Primary citation

Zhao, Y.,Mahy, W.,Willis, N.J.,Woodward, H.L.,Steadman, D.,Bayle, E.D.,Atkinson, B.N.,Sipthorp, J.,Vecchia, L.,Ruza, R.R.,Harlos, K.,Jeganathan, F.,Constantinou, S.,Costa, A.,Kjaer, S.,Bictash, M.,Salinas, P.C.,Whiting, P.,Vincent, J.P.,Fish, P.V.,Jones, E.Y.
Structural Analysis and Development of Notum Fragment Screening Hits.
Acs Chem Neurosci, 13:2060-2077, 2022

PubMed Abstract: The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 μM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1phenyl-1,2,3-triazole , and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound with IC 0.0067 μM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development.

PubMed: 35731924
DOI: 10.1021/acschemneuro.2c00325

Experimental method

X-RAY DIFFRACTION (1.52 Å)