The SPS and nSPS were compared to the frequently used complexity indices Fsp3, FCstereo, Böttcher complexity score Cm, Bertz total molecular complexity CT and Whitlock score S. The results for a set of representative compounds are shown in Table . Fsp3 and FCstereo are straightforward indicators, and therefore can often return the lowest possible score of 0 even for molecules with considerable topological complexity. Fsp3 can also often Table . Illustration of SPS partial scores for every atomic index in the depicted small molecule. The total SPS calculated for the compound is 364 and the nSPS is equal to 26.0. 𝑖 -atom index; ℎ -hybridisation term; 𝑠 -stereoisomeric term; 𝑟 -nonaromatic ring term; 𝑛 -heavy atom neighbours. yield the highest score of 1 for simple structures (Figure ). Additionally, a significant portion of small molecules does not have any stereogenic carbons, resulting in FCstereo scores of 0. Four different reference sets were curated and used for analysis, i.e. experimental and approved drugs from the DrugBank (DrugBank), the Enamine Advanced Screening Collection (Enamine, representing a commercial screening collection optimized for Lipinski's rule of five), natural products extracted from the ChEMBL database (ChEMBL NPs, representing bioactive natural products), and dark chemical matter (DCM, representing compounds that do not show activity in > 100 biological and biochemical assays). The results show that 56% of all structures have 1 or more stereogenic carbons, and,consequently, 44% of the molecules have an FCstereo score of 0 (Figure ). Thus, FCstereo is not an ideal indicator for comparisons and ranking between a significant number of compounds in such libraries. Unsurprisingly, Fsp3 and FCstereo indicators do not directly encapsulate many topological features such as the extent of skeletal branching or the presence of rings (see Table ), and thus, they are not comprehensive measures of complexity. In contrast, complexity scores like S, CT or Cm, are intended to comprehensively express the total molecular complexity. The Whitlock measure S does not differentiate well between compounds containing a smaller number of features, and is indifferent towards many important topological features including branching and ring sizes. On the other hand, the CT index expresses a number of topological nuances, but this scoring system is limited for instance by not taking chirality into account. Cm appears to score compounds in a more intuitive manner, easily distinguishing between linear, branched, saturated and unsaturated compounds with consideration for symmetry and elemental diversity. This complexity index, however, puts an emphasis on the presence of heteroatoms, as can be exemplified by comparison of n-hexane (size-normalised Cm by accounting for number of heavy atoms: Cm/HA of 2.2) with n-amyl bromide (Cm/HA of 6.3) or between more elaborate compounds such as rivaroxaban (Cm/HA of 15.9; compound 15 in Table ) and cholesterol (Cm/HA of 11.4; compound 16 in Table ).