Another notable method is l-dynamics, pioneered by Brooks and co-workers. It combines the idea of alchemical methods and US method by treating the l variable dynamically, and generates a potential of mean force in l-space. The initial application studies of alchemical methods were performed a few decades ago by a number of groups. Since this time, more and more significant applications in both academia and industry have been reported. However, to more reliably drive decisions in lead optimization, there are two major issues that alchemical methods should deal with, namely, adequate sampling of relevant configurations and force field accuracy. To address the sampling issues methods like Hamiltonian exchange and replica exchange have been developed, while improvements in force fields have been an