Evolutionary algorithms are typically very successful at generating and optimizing molecules, but they share a common drawback -synthesizability . To overcome this limitation RosettaEvolution-aryLigand (REvoLd) was developed to exploit large chemical combinatorial libraries to increase synthetic accessibility and to reduce at the same time the number of dockings required to discover highly potent molecules. Despite very promising results, REvoLd is currently limited to predefined chemical spaces defined by make-on-demand libraries. These specifications are typically protected by commercial interests and only accessible through non-disclosure agreements. Moreover, these spaces usually encompass quite simple molecules and include mostly chemical matter of limited interest due to their enormous size.