Although the benzothiazole and benzimidazole substructures share strong chemical similarity, the chemical diversity of FDA-approved drugs with these substructures is diverse, indicating that these substructures have been effectively used as scaffolds for generating specificity to various cellular targets for the treatment of various diseases (Supplementary Figure 4).
In an attempt to further improve the potency of 5 and explore new chemical space around the lead, we searched for compounds with: 1) a similar core scaffold to that of the lead and 2) a diverse selection of attached substructures that could probe and be accommodated within the large CYP121 water‐filled active‐site to enhance binding.
These substructures appear in diverse NSAIDs such as rofecoxib or etericoxib, as well as in chemical families of COX-2 inhibitors based on e.g. 1,5-diarylpyrazoles or 3,4-diaryl-substituted furans [23-25 [23-25
Notably, compounds in the Chembridge Diverse Set E library containing the substructure at node 7 are structurally homologous to three compounds present in the NCI library NSC636679 (21), NSC634791 (22) and NSC618757 (23) (Fig. 3C).
Diversity is, instead, diverse.
The potential applications of dynamically substructured systems (DSS) with both numerical and physical substructures can be found in diverse dynamics testing fields.
Given that the decision tree selected only 43 substructures out of 4860 available, many other privileged substructures are likely present in the Chembridge Diverse Set E library.
However, structural aspects of drugs are very diverse, and no catalog or database of characteristic substructures exists that includes most known active compounds.
Furthermore, the observation that privileged scaffolds contain diverse substituents suggests the broad activity associated with privileged substructures is the result of favorable scaffold entropy, while activity against a given target is determined by entropic contributions in combination with complementarity of shape and charge resulting from enthalpic contributions of substituents.
The level of SRD values (except for Superstructure and Substructure) is somewhat higher mostly in the case of diverse selection.
To assess reportedly privileged substructures and to identify new ones, we evaluated diverse high-throughput phenotypic assays applied to a commercially available chemical library.
