where R is the gas constant and T is the temperature of the system. RBFE is the difference in Δ𝐺 𝑏𝑖𝑛𝑑 ° of two ligands A and B, referred to as ∆Δ𝐺 𝐴→𝐵 . In drug design applications ABFE simulations can be used for initial screenings and hit identification of compounds for synthesis, while RBFE simulations are well-suited for hit-to-lead and lead optimization. A common approach to computing BFE is molecular dynamics (MD)-based thermodynamic integration (TI) that utilizes an "alchemical" i.e., nonphysical thermodynamic pathway. MD TI and other types of simulations that utilize an alchemical thermodynamic pathway to compute BFE are often termed alchemical binding free energy calculations. MD TI can be used to compute both ABFE and RBFE; however, the two methods have several technological differences in implementation, mainly in the alchemical pathways employed. MD TI simulations are expensive and technologically complex and, historically, scaling up these computations to include multiple ligands has been difficult.