The linking approach is intentionally basic as Fragmenstein is not intended for Protac design (i.e. two distinct moieties tethered by a long flexible linker) or to add novel chemical substructures between two hits. These use cases are addressed by other tools . A recent published approach, for example for fragment joining enumerate all purchasable compounds that contain substructure of pairs of hits and places these with Fragmenstein . For close compounds, the torsion of the link may be highly constrained by the substructures from the parent hits, which is exactly the sort of problem Fragmenstein can address as demonstrated in its role in the identification of a IC50 430 nM inhibitor against SARS-COV-2 Mac1 (mergers: ). Even though the compounds generated by combination are chemical correct, a limitation of this is that the compounds created may not be in make-on-demand space or may not be synthetically accessible. In the provided demonstration notebook the SmallWorld server is queried to find purchasable analogues from Enamine REAL (an analogues-by-catalogue approach) , which can be placed by Fragmenstein. A similar approach was used in the SARS-COV-2 Mac1 study (using Arthor, ). Chemical make-ondemand space despite its vastness is often limiting. In fact, it should be noted that the outcome of the search may not be always fruitful. For example, a merger of two perfectly placed parents may yield a compound that is far removed from make-on-demand space (e.g. Supplementary figure , a clear planar merger distant from make-on-demand space), thus forcing the user to consider other mergers or linkers as a starting point for exploration. Predictably, the more the lead-like candidates grow, the more isolated they may be in easily synthesisable chemical space. A fruitful synergism to optimise compounds is combing BRICS decomposition and Fragmenstein, which in effect removes substructures from the initial hits which are not forming good interactions or hamper synthetic accessibility. Beyond drug discovery, Fragmenstein has found uses in biochemistry settings by virtue of allowing the change of a crystallographically amenable analogue with the native substrate, e.g. the non-hydrolysable guanosine imidotriphosphate (GNP) for guanosine triphosphate (GTP) .