Linkerability of Protein Ligands: Insights From Cocrystal Structures and Implications for DNA-Encoded Libraries

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Structural Biology

Background:

• Linkers are vital in medicinal chemistry for applications like proximity inducers and DNA-encoded libraries (DEL).
• Understanding linker accessibility on protein-bound molecules is limited, hindering rational design.
• Assessing modifiable positions on ligands within protein-ligand complexes is essential for optimizing molecular design.

Purpose of the Study:

• To computationally evaluate the accessibility of modifiable positions on drug-like molecules for linker attachment within protein-ligand complexes.
• To quantify the geometric constraints influencing linker introduction and solvent-directed escape paths.
• To assess the impact of linker accessibility on DNA-encoded library (DEL) data quality and lead prediction.

Main Methods:

• Developed a computational workflow to assess linkerability based on solvent accessibility, local steric hindrance, and escape path geometry.
• Analyzed a large dataset of 8,228 protein-ligand cocrystal structures.
• Quantified modifiable positions (131,431) and their suitability for linker attachment.

Main Results:

• Approximately 22% of evaluated positions demonstrated sufficient accessibility for linker attachment without significant geometric restrictions.
• Significant geometric constraints were observed for many modifiable positions, limiting linker introduction.
• Limited linkerability impacts the quality and interpretation of DNA-encoded library (DEL) data.

Conclusions:

• The limited linker accessibility of protein-bound molecules is a critical factor affecting drug discovery efforts.
• Findings suggest that current DNA-encoded library (DEL) data may be influenced by linker attachment limitations.
• Improving the understanding and prediction of linker accessibility can enhance lead discovery and optimization strategies.