Covalent ligand efficiency

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Computational Chemistry

Background:

• Ligand efficiency (LE) is a key metric for noncovalent drug candidates, normalizing binding affinity by ligand size.
• Extending LE to irreversible covalent ligands is challenging due to the added dimension of reactivity.
• Existing metrics do not fully capture the complex binding and reactivity of covalent inhibitors.

Purpose of the Study:

• To develop and define a novel metric, covalent ligand efficiency (CLE), for evaluating irreversible covalent ligands.
• To incorporate both binding affinity and reactivity information into a single, comprehensive measure.
• To compare the utility of CLE against traditional LE for cysteine-targeting covalent ligands.

Main Methods:

• Analysis of noncovalent and covalent contributions to ligand-target interactions.
• Formulation of CLE, initially for cysteine-targeting ligands, using IC50 and glutathione (GSH) reactivity rate constants.
• Comparative analysis of LE and CLE across a dataset of over 6500 cysteine-targeting covalent ligands.

Main Results:

• A new metric, CLE, was successfully defined, integrating affinity and reactivity for covalent ligands.
• Comparative analysis demonstrated the distinct and informative nature of CLE compared to LE.
• The study validated the applicability of CLE for cysteine-targeting covalent inhibitors.

Conclusions:

• CLE offers a more accurate and comprehensive evaluation of covalent ligand performance than LE.
• The proposed metric provides valuable insights for the design and optimization of covalent drugs.
• CLE can be adapted for covalent ligands targeting residues other than cysteine by modifying the reactivity component.