Covalent ligand efficiency

Abstract

Ligand efficiency (LE) expresses the binding affinity of the ligand to its protein target normalized by ligand size. Although the concept is well established for noncovalent ligands, its extension to irreversible covalent ligands is not straightforward. Here, we analyze noncovalent and covalent contributions to the affinity and propose a new metric, named covalent ligand efficiency (CLE), which comprises affinity and reactivity information. CLE is originally defined for cysteine targeting ligands and its formula includes IC₅₀ against the target protein and reactivity rate constant toward glutathione (GSH). CLE and LE were comparatively analyzed for over 6500 cysteine-targeting covalent ligands. CLE can be extended to ligands targeting noncysteine residues by adjusting the reactivity contribution to the corresponding surrogate.