As we have shown in Case Study 1, the introduction of data generation, curation and sharing tools (QCFractal, QCArchive, QCSubmit), in combination with automated parametrization workflows (BespokeFit), opens the possibility of the routine use of bespoke parameter derivation in applications such as alchemical free energy calculations. In order to validate the use of OpenFF BespokeFit in such drug discovery efforts, we compute here relative binding free energies for a congeneric series of inhibitors of the TYK2 protein parametrized with BespokeFit derived FFs. Furthermore, to highlight the flexibility of the reference data generation via QCEngine, we derive FFs for the ligands from multiple sources, including the xTB semi-empirical method and QC at the OpenFF default specification level (Supporting Information Section S1.1).