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Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3β
Yikai Wang1, Jean-Yves Wach1, Patrick Sheehan1
1Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
ACS Medicinal Chemistry Letters
|September 24, 2016
Summary
Diversity-oriented synthesis (DOS) offers a novel fragment-based drug discovery (FBDD) strategy. This approach successfully identified initial hits against GSK3β and enabled the development of more potent compounds through analogue synthesis.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Synthetic Chemistry
Background:
- Traditional fragment-based drug discovery (FBDD) primarily uses structural analysis of target-bound fragments.
- A gap exists in exploring fragment-level structure-activity relationships (SAR) efficiently.
Purpose of the Study:
- To present diversity-oriented synthesis (DOS) as a complementary approach to traditional FBDD.
- To demonstrate the utility of DOS in identifying and optimizing fragment hits against a specific target.
Main Methods:
- A fragment collection was synthesized using diversity-oriented synthesis (DOS).
- The fragment collection was screened against the target GSK3β.
- Systematic synthesis of fragment analogues was performed to explore SAR.
- Optimization led to the development of a more potent compound.
Main Results:
- The DOS-based fragment collection yielded initial hit compounds against GSK3β.
- Fragment analogues were successfully synthesized, allowing for detailed SAR exploration.
- A more potent compound was ultimately synthesized through this iterative process.
Conclusions:
- Diversity-oriented synthesis (DOS) provides an effective alternative strategy for fragment-based drug discovery (FBDD).
- This method facilitates hit identification and systematic optimization of fragment leads.
- DOS enables efficient exploration of SAR at the fragment level, leading to improved compound potency.
