Carbonic anhydrases (CAs) are molecular targets in various diseases. While many sulfonamide-based drugs are in clinical use, CA inhibitor design is moving towards the incorporation of alternative zinc-binding groups, such as carboxylic acids, to promote CA isoform-specific inhibition. Here, X-ray crystal structures of CA II in complex with nicotinic acid and ferulic acid determined to 1.70 and 1.50 Å resolution, respectively, are reported. Furthermore, the structures of these two compounds are superimposed with previously determined structures to compare the mechanisms of inhibition and the properties of carboxylic acid-based CA inhibitors. This study examines an important class of alternative, non-sulfonamide-based CA inhibitors and provides insight to facilitate the structure-guided design of CA isoform-specific inhibitors.
Keywords: carbonic anhydrase II; carboxylic acids; structure-guided drug design.