In addition to ignoring all non-cyclic molecules, the Murcko framework has one major drawback: small changes in the ring structure or the addition of a cyclic substituent, e.g. a benzene ring in drug design or a sugar moiety in NP research, can lead to very similar molecules not being grouped together due to non-equivalent scaffolds. Therefore, multiple approaches have been developed for organising molecular scaffolds in a graph-based structure to relate similar scaffolds to each other and to create a systematic scaffold hierarchy .