Analysis of the scaffold content of the compound datasets revealed that compounds in NAPROC-13 present a high content of cyclic compounds, with a small fraction (0.78%) of acyclic structures. In contrast, NPs in UNPD-A, as well as FDA-approved drugs, have a similar fraction of acyclic compounds, nearly 11.5% of the database. However, it is remarkable that most of the cyclic molecular cores in NAPROC-13 are uniquely present in NAPROC-13 (see Figure and Figure in the Supporting Information). Moreover, most of them are absent in the compounds approved for clinical use. The large abundance of merged aromatic and saturated rings for almost all the fifteen most frequent scaffolds in NAPROC-13 is noticeable. An exception to this trend is the high content of benzene-type rings, with 208 (0.98%) substructures, which tend to be the most frequent scaffold in small-molecule databases, specifically in NPs, and even food chemicals. NAPROC-13 presented 8169 molecular scaffolds, 77 common to all three databases, 1770 shared with UNPD-A (the highest overlapping in scaffold analysis), and 84 shared with FDA-approved drugs. UNPD-A had 7059 scaffolds, 5175 were unique, and 191 were shared with FDA-approved drugs. Finally, FDAapproved drugs had 1291 scaffolds, and 1093 of them were unique. These results are in accordance with the high molecular diversity in NPs, demonstrated by pairwise similarity relationships (see above), and with previous analyses of the databases analyzed in this study. Quantitative approaches to compare the scaffold diversity of compound datasets are the SSE and the CSR curve. The scaled SSE is an index that measures how the information, in this case, compounds, are distributed along the different scaffolds, in terms of uniformity. The SSE ranges from zero (no diversity since all compounds share the same scaffold) to one (maximum diversity, uniform distribution of compounds along the scaffolds). For the three databases compared in the present study, NAPROC-13 presented an SSE of 0.97 for their fifteen most frequent scaffolds (chemical structures shown in Figure ), FDA-approved drugs 0.63, and UNPD-A 0.67. These values of SSE indicate that there is no evident predominance among the first fifteen scaffolds in NAPROC-13 NPs. In contrast, for UNPD-A NPs as well as FDA-approved drugs, saturated and unsaturated six-membered rings are overrepresented, which can be noticeable in SSE. These results are in agreement with previous studies. The CSR curves shown in Figure are a graphic representation of how compounds -represented as the fraction of each database-are distributed along the set of scaffolds, represented as the fraction of the total amount of scaffolds. As more compounds are accumulated by a small fraction of the database's scaffolds, the less diverse the database is. The CSR curves in Figure indicate that the FDA-approved drugs set has the overall largest scaffold diversity, followed by UNPD-A, and finally by NAPROC-13. These measures support the previously discussed high diversity of NPs.