Building Block-Centric Approach to DNA-Encoded Library Design.

Area of Science:

• Medicinal Chemistry
• Drug Discovery Technology
• Chemical Biology

Background:

• DNA-encoded library (DEL) technology provides access to vast chemical structure space for drug discovery.
• Designing effective DELs requires balancing physicochemical properties (PCPs), structural diversity, and practical synthesis constraints.
• Understanding combinatorial library design, including chemistry cycles and building block (BB) selection, is crucial for successful navigation.

Purpose of the Study:

• To analyze combinatorial library design constraints in DELs for optimal library generation.
• To compare two-cycle DEL designs (amino acid + carboxylic acid, primary amine + carboxylic acid) regarding PCPs and chemical space coverage.
• To evaluate the impact of building block selection strategies and constraints on DEL design.

Main Methods:

• Analysis of combinatorial library design constraints: number of chemistry cycles, bond construction strategies, and BB class selection.
• Comparison of two-cycle DEL designs using amino acid + carboxylic acid and primary amine + carboxylic acid building blocks.
• Evaluation of physicochemical properties (PCPs) and chemical space coverage under different BB selection strategies and constraints.

Main Results:

• Broad availability of amine and carboxylic acid building blocks is essential for exploring the widest chemical space.
• Cost is not a primary driver for chemical space exploration; similar chemical space can be accessed with less expensive building blocks.
• Two-cycle library designs demonstrate that BB class selection significantly impacts PCP and diversity.

Conclusions:

• Strategic selection of diverse and readily available building blocks, particularly amines and acids, is key for maximizing chemical space in DELs.
• DEL design should prioritize BB diversity over cost to achieve optimal chemical space coverage and drug discovery potential.
• The findings provide practical guidance for designing efficient and effective DNA-encoded libraries.