Linkerability of Protein Ligands: Insights From Cocrystal Structures and Implications for DNA‐Encoded Libraries
Linkers play a central role in many areas of medicinal chemistry, including proximity inducers, small‐molecule conjugates, and DNA‐encoded libraries. However, little is known about the accessibility of molecules to linker attachment when bound to proteins. Here, we analyze linker accessibility across protein–ligand complexes in cocrystal structures. A computational workflow was developed to evaluate the linkerability of modifiable positions on molecules based on solvent accessibility, local steric space for introduction of a linker atom, and the geometry of solvent‐directed escape paths approximated as conical frustums. Analysis of 8,228 protein–ligand cocrystal structures with 131 431 modifiable positions shows that approximately 22% of positions can accommodate linkers without significant geometric restriction. Limited linkerability of positions influences DEL data and may confound efforts to use such data for lead prediction.