In the parameter study, the cases where W F = True, S F = True, and N F in equals 40, 50, and 500, respectively, exhibit the most promising fragment libraries. To be more precise, when W F and S F are activated, the effect of varying N F in can be neglected. However, when either of these two parameters is deactivated, increasing N F in negatively impacts the performance of the genetic algorithm. In summary, a fragment library with activated weighting and substitution parameters has a positive impact on the Design phase in the warm-started COSMO-CAMD framework.