Early-stage drug discovery needs accurate computational methods to help guide and accelerate the drug discovery process. However, drugs commonly have dissociation rate constants of 10 -1 to 10 -6 𝑠 -1 (Holdgate, 2017), making it impractical to directly simulate binding and unbinding events with conventional molecular dynamics (MD). These slow unbinding events make alternative routes for affinity estimation appealing. In particular, so-called alchemical simulations provide a method to compute free energy differences between the bound and unbound states. Since free energy is a state function, we can measure changes in free energy with alternative binding and unbinding pathways via non-physical ("alchemical") intermediates. Ultimately, suitable alchemical simulations measure the change in Gibbs free energy, Δ𝐺, which for binding is related to ligand affinity. Alchemical simulations can then avoid some of the slow sampling associated with direct MD, making alchemical methods an attractive tool for drug discovery.