CASE Plots for the Chemotype-Based Activity and Selectivity Analysis: A CASE Study of Cyclooxygenase Inhibitors

Structure–activity characterization of molecular databases plays a central role in drug discovery. However, the characterization of large databases containing structurally diverse molecules with several end‐points represents a major challenge. For this purpose, the use of chemoinformatic methods plays an important role to elucidate structure–activity relationships. Herein, a general methodology, namely Chemotype Activity and Selectivity Enrichment plots, is presented. Chemotype Activity and Selectivity Enrichment plots provide graphical information concerning the activity and selectivity patterns of particular chemotypes contained in structurally diverse databases. As a case study, we analyzed a set of 658 compounds screened against cyclooxygenase‐1 and cyclooxygenase‐2. Chemotype Activity and Selectivity Enrichment plots analysis highlighted chemotypes enriched with active and selective molecules against cyclooxygenase‐2; all this in a simple 2D graphical representation. Additionally, the most active and selective chemotypes detected in Chemotype Activity and Selectivity Enrichment plots were analyzed separately using the previously reported dual activity–difference maps. These findings indicate that Chemotype Activity and Selectivity Enrichment plots and dual activity–difference maps are complementary chemoinformatic tools to explore the structure–activity relationships of structurally diverse databases screened against two biological end‐points. Chemotype Activity and Selectivity Enrichment (CASE) plots are presented in this work as a novel graphical representation of the chemical structure, activity and selectivity of a molecular database with activity against two biological endpoints. Compounds with selected chemotypes (most active and selective) were further characterized using Dual Activity Difference (DAD) maps. The application of both methodologies leads to a comprehensive SAR analysis comprising scaffolds and side chains for a set of cyclooxygenase inhibitors.