Chemical Space Exploration of a Database of Covalent Binders in the PDB

Covalent binders (CBs) represent a broad and increasingly important class of compounds with substantial clinical potential. Although they have historically been overlooked because of toxicity concerns, covalent inhibitors are now recognized as a valuable therapeutic strategy with important pharmacological implications. While the chemical diversity of CBs has been well documented, their comprehensive characterization in terms of chemical space and enzyme class remains underexplored. In this study, we present a systematic analysis of CBs available in the Protein Data Bank (PDB) grouped by their biological target. Our extensively curated database includes 3,585 chemical structures deposited in the PDB, significantly expanding the chemical space representation of CBs. We explore this space using therapeutically relevant targets in medicinal chemistry as case studies, highlighting the breadth and specificity of covalent interactions captured in the updated dataset. Furthermore, we compare the chemical space of CBs with key reference datasets, including approved drugs, natural products, and fragment libraries. This comparison underscores the unique and complementary roles that CBs play in drug discovery. The updated database of CBs, freely available to the scientific community, provides a valuable resource to support the rational design and development of covalently binding therapeutic agents.