Journal of medicinal chemistry

The coumarin-binding site in carbonic anhydrase accommodates structurally diverse inhibitors: the antiepileptic lacosamide as an example and lead molecule for novel classes of carbonic anhydrase inhibitors.

PMID 20028100


Coumarins constitute a general and totally new class of inhibitors of the zinc enzyme carbonic anhydrase (CA, EC, binding at the entrance of the active site cavity. We report here that the coumarin-binding site in CAs may interact with diverse compounds, such as the antiepileptic drug lacosamide, which inhibits mammalian CAs I-XV, with inhibition constants in range of 331 nM to 4.56 microM. Its X-ray crystal structure in adduct with CA II reveals the molecular basis for this inhibition. Lacosamide was found in the coumarin-binding site, making favorable van der Waals interactions with Thr200, Asn67, Gln92, and Phe131. No interactions with the Zn(II) ion were evidenced in the CA II-lacosamide adduct. The coumarin-binding site may thus accommodate structurally diverse compounds which possess an inhibition mechanism distinct of that of sulfonamides. This finding opens new possibilities for designing CA inhibitors/activators with various biomedical applications.