Free energy calculations were used to generate training targets in the prospective dataset (Part II). These calculations were based on the molecular dynamics simulations relying on the non-equilibrium free energy calculation protocol . The perturbation maps were constructed using a star shaped map topology , where a single ligand with the experimentally measured binding affinity and common scaffold with the rest of the compounds was used as a reference for all perturbations. All the ligands were considered in their neutral form using a single tautomer, as generated by RDKit. First, the ligands were parameterized with GAFF 1.81 using ACPYPE and AnteChamber 52 with AM1-BCC charges and off-site charges for halogen atoms . A hybrid topology was then built for each evaluated ligand against the reference ligand with pmx .