SPS and nSPS are indifferent to the elemental constitution of molecules (compare 2 and 3 in Table ) and penalise unsaturation (compare 1 and 3), unless it contributes to the isomeric diversity (compound 5). Branched and non-aromatic cyclic molecules are awarded higher scores than linear structures (e.g. compare compounds 3 and 4, as well as 2 and 12), and stereogenic atoms are stressed (compound 7). Comparison of the nSPS of cholesterol (46.5) to the nSPS of rivaroxaban (19.4; Table ), as well as various molecules at different nSPS ranges (Figure and S4), matches general intuition concerning the intricacy of spatial arrangements in these molecules. We also calculated and compared Fsp3, FCstereo and nSPS for each of the synthesised compounds in the total synthesis of (-)-bilobalide by Demoret et al., further substantiating our conclusion regarding the intuitive nature of the new scoring system and combined improvement over Fsp3 and FCstereo as individual descriptors (Figure ). Assessment of Pearson correlation coefficients of nSPS with basic molecular descriptors for a collection of representative molecules from DrugBank-, Enamine-, ChEMBL NP-, and DCM reference sets revealed that, as designed, the score is highly correlated with Fsp3 (0.68) and FCstereo (0.83) and negatively correlated with the sizenormalised number of aromatic rings (-0.62; Figure ). Further analysis showed that in order to reach high nSPS, compounds need to have high Fsp3 scores; however, high Fsp3 scores do not necessarily translate to large nSPS values (Figure ). Similarly, not all compounds with high FCstereo are complex as determined based on the corresponding nSPS, and molecules with FCstereo of 0 can also have elaborate topology as discussed above (Figure ). No correlation with the size-normalised approximate surface area (ASA), number of hydrogen bond donors and acceptors, estimated clogP values, and quantitative estimate of drug-likeness (QED) was observed. However, we noted a significant correlation (0.69) with natural product-likeness (NP-likeness), as well as a moderate degree of correlation (0.4) with the plane of best fit (PBF) score (Figure ). The relationship with the PBF score, although not significantly stronger than what is observed for Fsp3 and FCstereo, is interesting, as calculations of PBF are normally computationally demanding due to the necessity to accurately predict the representative 3D conformations of the investigated molecules.