A simple method for determining compound affinity and chemical yield from DNA-encoded library selections.

Area of Science:

• Medicinal Chemistry
• Biotechnology
• Computational Chemistry

Background:

• DNA-encoded libraries (DELs) enable screening of billions of compounds.
• Identifying high-affinity binders from large DEL outputs is challenging.
• Accurate estimation of binder potential is crucial for efficient drug discovery.

Purpose of the Study:

• To develop theoretical methods and equations relating DEL selection signal strength to compound affinity and chemical yield.
• To provide a framework for prospectively evaluating candidate binders from DEL screens.

Main Methods:

• Formulation of theoretical equations linking selection signal, affinity, and chemical yield.
• Experimental validation of the theoretical models using known binders for BRD4 and ROCK2 targets.

Main Results:

• The developed equations accurately predict the theoretical selection signal based on affinity and chemical yield.
• Experimental data supports the theoretical framework, demonstrating its utility.

Conclusions:

• The established methods provide a quantitative approach to assess candidate binders in DEL selection.
• These findings facilitate more efficient prioritization of compounds for synthesis and testing, improving drug discovery pipelines.