Fig. 2.

Molecular diversity of the NINDS-II compound collection screened in this study. (A) Relationship between a molecule and its scaffold, using tranilast as an example. The scaffold or cyclic system is obtained after iteratively removing the side chains and is identified by a five-character chemotype identifier code. The WSLAM scaffold is a singleton, i.e. tranilast is the only compound in the collection with this scaffold. (B) Scaffold-recovery curve. The x-axis represents the scaffolds, organized left-to-right from the most common (benzene) to the singletons, plotted as a cumulative fraction of the total (552, with all 66 acyclic systems considered a single scaffold). The y-axis shows the cumulative fraction of the 1040 compounds occupied by a given fraction of the scaffolds: ∼14% of the scaffolds contain 50% of the NINDS-II library (red lines), and 60% of the library is distributed over ∼24% of the scaffolds (green lines). Beyond this point, each scaffold is a singleton and the relationship becomes linear. (C) Common scaffolds in the NINDS-II library. 2D representations of cyclic systems found with a frequency ≤5; the number is under each structure. Highlighted are the pyridines (red), the quinolines (blue), and the scaffolds containing a four-ring sterol (green; 36 compounds). (D) Representation of chemical fingerprint analysis based on MACCS keys, using the antipsychotic drug droperidol as an example. Each of 166 possible substructural features is coded using a bit score: present at least once (1) or absent (0). Four of droperidol’s features (CN₂O, fluorine, five-membered heterocycle and C₃N) are shown with their positions in the MACCS keys bitstring. (E,F) 3D representations of the NINDS-II library in chemical space, obtained by principal component analysis (PCA) of the similarity matrix computed using MACCS keys and Tanimoto similarity. Each compound is shown as a sphere. The chemical space distribution of the compounds is extensive, with regional variation in population density. The 17 antipsychotic drugs (blue), are localized to a medium-sized sector of the space and interspersed among compounds with other activities. This is consistent with these drugs occupying 14 scaffolds and representing several different pharmacological mechanisms of action. (E) View centered on the vertical (PCA 2) axis. (F) The view obtained by rotation around the vertical axis. One antipsychotic drug is hidden behind another compound.