Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
J Med Chem. 2010 Jan 28;53(2):850-4. doi: 10.1021/jm901524f.
Coumarins constitute a general and totally new class of inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), 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.
香豆素是一类全新的锌酶碳酸酐酶（CA，EC 4.2.1.1）抑制剂，它们结合在活性位点腔的入口处。我们在此报告，CA 中的香豆素结合位点可能与多种化合物相互作用，如抗癫痫药物拉科酰胺，它抑制哺乳动物 CA I-XV，抑制常数范围为 331 nM 至 4.56 μM。其与 CA II 的 X 射线晶体结构揭示了这种抑制的分子基础。拉科酰胺被发现在香豆素结合位点，与 Thr200、Asn67、Gln92 和 Phe131 形成有利的范德华相互作用。在 CA II-拉科酰胺加合物中没有证据表明与 Zn(II)离子相互作用。因此，香豆素结合位点可以容纳结构多样的化合物，它们具有与磺胺类药物不同的抑制机制。这一发现为设计具有各种生物医学应用的 CA 抑制剂/激活剂开辟了新的可能性。
