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Exploring protein hotspots by optimized fragment pharmacophores
Dávid Bajusz1, Warren S Wade2, Grzegorz Satała3
1Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary.
Nature Communications
|May 28, 2021
Summary
Fragment-based drug design is enhanced by SpotXplorer, a new protocol for creating fragment libraries. This method maximizes coverage of drug-target interactions at protein hotspots, improving early drug discovery.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Drug Discovery
Background:
- Fragment-based drug design (FBDD) offers a bottom-up approach to drug development.
- FBDD improves chemical space sampling and early-stage drug discovery effectiveness.
Purpose of the Study:
- To develop a novel design protocol for fragment libraries.
- To combine pharmacophores and protein hotspot theory for optimized fragment library design.
Main Methods:
- The SpotXplorer approach was developed to compile small fragment libraries.
- Libraries are designed to maximize coverage of experimentally confirmed binding pharmacophores at preferred protein hotspots.
- A pilot library (SpotXplorer0) of 96 compounds was created and validated.
Main Results:
- Biochemical screening of SpotXplorer0 against GPCRs and proteases yielded compounds with an average of 70% of known target pharmacophores.
- Screening identified confirmed hits against challenging targets including SETD2, 3CLPro, and SARS-CoV-2 NSP3 macrodomain.
Conclusions:
- The SpotXplorer approach enables the creation of efficient fragment libraries.
- This strategy is effective for both established and emerging drug targets, including those from SARS-CoV-2.
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