Binding Free Energy Calculations in Drug Discovery

This chapter attempts to provide an overview of the different approaches and methods that are available to compute free-energy differences in drug design and drug discovery. Numerous methods for the calculation of binding free energies have been developed over the years. As the name implies, endpoint methods only require the simulation of the endpoints of the system of interest. The chapter discusses two kinds of endstate methods: the molecular mechanics Poisson–Boltzmann surface area methods and methods derived from linear response theory. Once one or more lead compounds have been discovered during the early stages of drug discovery, lead optimization can be performed with more rigorous alchemical methods. The pathway methods give an insight into the (relative) binding free energy, the binding poses, and the interactions between the ligand and protein.