As an alternative to 2-D similarity search, 3-D similarity search can also be performed using the “3D conformer” tab in PubChem Chemical Structure Search. 3-D similarity methods use the 3-D structures (that is, conformations) of molecules. PubChem’s 3-D similarity method is based on the atom-centered Gaussian-shape comparison method by Grant, Gallardo and Pickup, implemented in the Rapid Overlay of Chemical Structures (ROCS). While the underlying mathematics of this approach is beyond the scope of this module, what this method essentially does is to find the "best" alignment of the 3-D structures of two molecules, which gives the maximized overlap between them. The 3-D similarity method quantifies the 3-D molecular similarity using three metrics.
- Shape-Tanimoto (ST): quantifies steric shape similarity between two conformers.
- Color-Tanimoto (CT): quantifies the overlap of functional groups between two conformers, such as hydrogen bond donors and acceptors, cations, anions, rings, and hydrophobes.
- Combo-Tanimoto (ComboT): the sum of ST and CT scores between two conformers. It takes into account the shape similarity (ST) and functional group similarity (CT) simultaneously.
Because both the ST and CT scores range from 0 (for no similarity) to 1 (for identical molecules), the ComboT score may have a value from 0 to 2 (without normalization to unity). Note that the ST, CT and ComboT scores between two molecules can be evaluated in two different molecular superpositions: (1) in the ST- or shape-optimized superpositions, and (2) in the CT- or feature-optimization superpositions. In the ST-optimization approach, the shape overlap between the molecules (that is, the ST score) is maximized and the single-point CT score is evaluated at that superposition. On the contrary, the CT-optimization considers both ST and CT scores to find the best superposition between molecules, and the single-point ST score is computed at that superposition.