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Development of a Selection Method for Discovering Irreversible (Covalent) Binders from a DNA-Encoded Library
Zhengrong Zhu1, LaShadric C Grady1, Yun Ding1
11 GlaxoSmithKline, Cambridge, Massachusetts, USA.
SLAS Discovery : Advancing Life Sciences R & D
|November 2, 2018
Summary
This study introduces a new DNA-encoded library (DEL) method to discover irreversible covalent ligands, a unique drug discovery approach. The method successfully identified covalent inhibitors using 3C protease, outperforming traditional techniques.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Drug Discovery
Background:
- DNA-encoded libraries (DELs) are powerful tools for identifying reversible ligands.
- Irreversible (covalent) inhibition presents a distinct mechanism for drug development.
- Existing DEL methods primarily focus on reversible ligand discovery.
Purpose of the Study:
- To develop and validate a novel method for identifying irreversible (covalent) ligands using DELs.
- To demonstrate the efficacy of this new DEL approach for covalent drug discovery.
- To compare different immobilization techniques for DEL affinity selections.
Main Methods:
- Utilized DNA-encoded libraries (DELs) for affinity selection against 3C protease (3CP).
- Employed on-DNA irreversible tool compounds (rupintrivir derivatives) spiked into the library.
- Compared microscale columns with magnetic beads for compound immobilization and recovery.
Main Results:
- The novel DEL method successfully identified and enriched specific irreversible tool compounds.
- Irreversible tool compounds showed significantly higher enrichment compared to standard library members.
- Microscale columns demonstrated superior tool compound recovery compared to magnetic beads.
Conclusions:
- A new DEL method enables the discovery of irreversible covalent ligands.
- This approach expands the utility of DELs beyond reversible ligand identification.
- Optimized immobilization strategies, such as microscale columns, enhance DEL method efficiency.
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