Due to the congeneric nature of the series, it is easy to see that there is a common core shared between the TYK2 ligands used in this study, and this core is also identified by the fragmentation procedure as being electronically decoupled from the proposed substitutions. To save parametrization time, the internal parameter caching system of BespokeFit was used to process a single molecule (id ejm-31) to generate a set of shared, core parameters. For the remaining molecules, bespoke parameters were only derived for new substitutions, in the presence of the optimized common core parameters. This reduces the parameter optimization time as the three rotatable bonds of the central core, and their corresponding 32 free parameters, do not need to be re-optimized for each of the 16 ligands in the series. geometries (still measured relative to the default QC scans).