Mechanism-Based and Computational-Driven Covalent Drug Design.

Covalent drugs offer higher efficacy and longer duration of action than their noncovalent counterparts. Significant advances in computational methods for modeling covalent drugs are poised to shift the paradigm of small molecule therapeutics within the next decade. This viewpoint discusses the advantages of a two-state model for ranking reversible and irreversible covalent ligands and of more complex models for dissecting reaction mechanisms. The relation between these models highlights the complexity and diversity of covalent drug binding and provides opportunities for mechanism-based rational design.