Carbonic anhydrase II in complex with carboxylic acid-based inhibitors

Abstract

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.

Aspirin: A Suicide Inhibitor of Carbonic Anhydrase II

“…Using molecular modeling, it can be hypothesized that Aspirin would bind in a similar fashion to nicotinic and ferulic acid within the active site of CAII, priming its ester group for nucleophilic attack (Figure 3) [16]. The fast rate of conversion from Aspirin to SA has made it difficult to obtain the crystal structure of the Aspirin-CAII complex [16]. Using molecular modeling, it can be hypothesized that Aspirin would bind in a similar fashion to nicotinic and ferulic acid within the active site of CAII, priming its ester group for nucleophilic attack (Figure 3) [16].…”

“…The fast rate of conversion from Aspirin to SA has made it difficult to obtain the crystal structure of the Aspirin-CAII complex [16]. Using molecular modeling, it can be hypothesized that Aspirin would bind in a similar fashion to nicotinic and ferulic acid within the active site of CAII, priming its ester group for nucleophilic attack (Figure 3) [16]. The fast rate of conversion from Aspirin to SA has made it difficult to obtain the crystal structure of the Aspirin-CAII complex [16].…”

“…Using molecular modeling, it can be hypothesized that Aspirin would bind in a similar fashion to nicotinic and ferulic acid within the active site of CAII, priming its ester group for nucleophilic attack (Figure 3) [16]. The fast rate of conversion from Aspirin to SA has made it difficult to obtain the crystal structure of the Aspirin-CAII complex [16]. Similarly to SA, Aspirin is predicted to bind through the zinc bound solvent.…”

“…In addition to sulfonamides, a variety of other chemical motifs have been identified to inhibit CA, such as carboxylic acids [15]. Nicotinic and ferulic acid have recently been identified as inhibitors of CAII [16]. Unlike the sulfonamide-based drugs, these inhibitors do not directly displace the zinc bound solvent, but instead anchor through the solvent, blocking substrate entry to the active site [16].…”

“…Nicotinic and ferulic acid have recently been identified as inhibitors of CAII [16]. Unlike the sulfonamide-based drugs, these inhibitors do not directly displace the zinc bound solvent, but instead anchor through the solvent, blocking substrate entry to the active site [16]. Furthermore, 3-nitrobenzoic acid has also been reported as a potent CAI, with further studies showing its potential clinical relevance as a cancer therapeutic [17].…”