Diversity-oriented synthesis encoded by deoxyoligonucleotides

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Diversity-oriented synthesis (DOS) generates molecules with unique structural features.
• DNA-encoded libraries (DELs) are effective for screening protein binders but often limited by DNA construct sensitivity.
• Current DEL syntheses can be restricted in structural diversity, often relying on appendage variation.

Purpose of the Study:

• To design and synthesize a large, structurally diverse DNA-encoded library using DOS principles.
• To overcome limitations of traditional DEL synthesis by incorporating diverse skeleton architectures and exit vectors.
• To demonstrate the utility of this novel DEL for screening against protein targets and accelerate early-phase drug discovery.

Main Methods:

• Utilized diversity-oriented synthesis (DOS) strategies to build complex molecular scaffolds.
• Developed a 3.7 million-member DNA-encoded library (DEL) with varied skeleton architectures and exit vectors.
• Performed screening experiments against three diverse protein targets to validate library utility.

Main Results:

• Successfully generated a large DEL (3.7 million members) with significant structural diversity beyond appendage variation.
• Demonstrated the effectiveness of the DOS-derived DEL in identifying protein binders.
• Obtained screening results for three distinct protein targets, showcasing the library's applicability.

Conclusions:

• The developed DOS-based DEL significantly expands structural diversity accessible through DEL technology.
• This approach overcomes limitations associated with sensitive DNA constructs in traditional DEL synthesis.
• The DEL will be made available to the scientific community to foster early-phase drug discovery and identify novel biological mechanisms.