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NMR-Based Fragment Screening in a Minimum Sample but Maximum Automation Mode
Published on: June 4, 2021
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Structural Analysis and Development of Notum Fragment Screening Hits
Yuguang Zhao1, William Mahy2, Nicky J Willis2
1Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, U.K.
ACS Chemical Neuroscience
|June 22, 2022
Summary
Researchers identified novel inhibitors for Notum, a target for diseases like Alzheimer's and cancer. Fragment screening yielded promising compounds, including 7d with potent inhibitory activity, paving the way for new drug development.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Structural Biology
Background:
- Notum is a key suppressor of Wnt signaling, implicated in osteoporosis, Alzheimer's disease, and colorectal cancers.
- Developing specific Notum inhibitors is crucial for therapeutic intervention in these diseases.
Purpose of the Study:
- To discover and optimize novel small-molecule inhibitors of Notum using fragment-based drug discovery.
- To characterize the binding modes and inhibitory potencies of identified fragments.
Main Methods:
- X-ray crystallography was employed for fragment screening using the Diamond-SGC Poised Library (DSPL).
- 768 data sets were analyzed to identify fragment hits binding to the Notum catalytic pocket.
- Hit optimization involved structure-activity relationship studies and chemical modifications.
Main Results:
- 59 fragment hits were identified, with 58 binding to the enzyme's catalytic pocket.
- Fragment potencies ranged from 0.5 to >1000 microM, with six selected for optimization.
- Optimization led to compound 7d, exhibiting a potent IC50 of 0.0067 microM and promising lead-like properties.
Conclusions:
- Fragment-based screening is an effective strategy for identifying Notum inhibitors.
- The identified fragment series, particularly compound 7d, provides a strong foundation for further development of Notum-targeted therapeutics.
- Structural insights from fragment binding aid in rational drug design for Notum inhibitors.
