Abstract: The invention relates to a system, method, and computer program for estimating binding affinity that is purely physics-based, highly accurate, computationally efficient, and applicable to drugs of any size and proteins of any flexibility level. In one aspect, a method for physics-based binding affinity estimation is disclosed. The method includes the step of creating a unified simulation for a ligand and a target molecule, where the unified simulation includes a plurality of replicas that are each associated with four restraints along four variables. The method also includes the steps of exchanging data for the four variables between a subset of the replicas and performing a single non-parametric reweighting analysis with the data to estimate an absolute binding free energy for the ligand and target molecule.