Free Energy Calculations in Covalent Drug Design

Covalent inhibition has been attracting significant attention in drug discovery. Here we present the free energy-based computational modeling of both reversible and irreversible covalent inhibitors. The specific features of reversible inhibition are discussed emphasizing the difference between the two-state noncovalent and the three-state reversible covalent inhibition. Computational approaches and approximations to calculate the free energy differences among the states are discussed together with the relationship between computed free energies and inhibitory activities. The computational schemes for producing complete free energy profiles for irreversible inhibition are also presented. The combined application of classical molecular dynamics (MD) for the equilibrium process of noncovalent complex formation and the QM/MM-based simulation of the chemical reaction for covalent complex formation is discussed. Publications presenting case studies of computed free energy-based characterization of inhibitory activities are reviewed.