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.