Similar compounds versus similar conformers: complementarity between PubChem 2-D and 3-D neighboring sets.

The results of our study indicate that, for the majority of the compounds in PubChem, their structural similarity to other compounds can be recognized predominantly by either 2-D or 3-D neighborings, but not by both, showing a strong complementarity between 2-D and 3-D neighboring results. Therefore, despite its heavy requirements for computational resources, 3-D neighboring provides an alternative way in which the user can instantly access structurally similar molecules that cannot be detected if only 2-D neighboring is used.Graphical AbstractThe binned distribution of the neighbor preference indices (NPIs) for all compounds in PubChem (left) has a bimodal shape with two maxima at NPI = ±1 and a minimum at NPI = 0, indicating that structural similarity between compounds in PubChem can be recognized predominantly by either 2-D or 3-D neighborings, but not by both. The NPI histogram for the drug space (right) has a greater fraction of compounds with a strong preference for one neighboring method to the other (at NPI ≈ ±1) as well as compounds with a neutral preference (at NPI ≈ 0), indicating that the drug space is very different from the PubChem space.