Fraction sp3 (Fsp3) values were used to compare the flatness of known scaffolds (used as privileged structures, drug scaffolds, and in scaffold-hopping approaches) and natural product (NP) scaffolds. The vast majority of the known synthetic scaffolds are planar with Fsp3 values/0.45 while the NP scaffold set is composed of mainly non-flat scaffolds. The identification of new or novel scaffolds to provide libraries of small diverse bioactive compounds is of the utmost importance to chemical biology and medicinal chemistry research. Non-flat scaffolds embedded in NPs may explore neglected areas of chemical space. We performed a scaffold abstraction from the dictionary of natural products (DNP), which resulted in 15,822 scaffolds. From this scaffold set, the vast majority (70 %), are non-flat scaffolds with Fsp3 value[0.45. These non-flat scaffolds may cover 83 % of ring systems that are absent from screening set.