Weber Alexander, Casini Angela, Heine Andreas, Kuhn Daniel, Supuran Claudiu T, Scozzafava Andrea, Klebe Gerhard
Department of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
J Med Chem. 2004 Jan 29;47(3):550-7. doi: 10.1021/jm030912m.
By optimizing binding to a selected target protein, modern drug research strives to develop safe and efficacious agents for the treatment of disease. Selective drug action is intended to minimize undesirable side effects from scatter pharmacology. Celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx) are nonsteroidal antiinflammatory drugs (NSAIDs) due to selective inhibition of inducible cyclooxygenase COX-2 while sparing inhibition of constitutive COX-1. While rofecoxib contains a methyl sulfone constituent, celecoxib and valdecoxib possess an unsubstituted arylsulfonamide moiety. The latter group is common to many carbonic anhydrase (CA) inhibitors. Using enzyme kinetics and X-ray crystallography, we demonstrate an unexpected nanomolar affinity of the COX-2 specific arylsulfonamide-type celecoxib and valdecoxib for isoenzymes of the totally unrelated carbonic anhydrase (CA) family, such as CA I, II, IV, and IX, whereas the rofecoxib methyl sulfone-type has no effect. When administered orally to glaucomatous rabbits, celecoxib and valdecoxib lowered intraocular pressure, suggesting that these agents may have utility in the treatment of this disorder. The crystal structure of celecoxib in complex with CA II reveals part of this inhibition to be mediated via binding of the sulfonamide group to the catalytic zinc of CA II. To investigate the structural basis for cross-reactivity of these compounds between COX-2 and CA II, we compared the molecular recognition properties of both protein binding pockets in terms of local physicochemical similarities among binding site-exposed amino acids accommodating different portions of the drug molecules. Our approach Cavbase, implemented into Relibase, detects similarities between the sites, suggesting some potential to predict unexpected cross-reactivity of drugs among functionally unrelated target proteins. The observed cross-reactivity with CAs may also contribute to differences in the pharmacological profiles, in particular with respect to glaucoma and anticancer therapy and may suggest new opportunities of these COX-2 selective NSAIDs.
通过优化与选定靶蛋白的结合，现代药物研究致力于开发安全有效的疾病治疗药物。选择性药物作用旨在将分散药理学产生的不良副作用降至最低。塞来昔布（西乐葆）、伐地昔布（Bextra）和罗非昔布（万络）是通过选择性抑制诱导型环氧化酶COX - 2同时避免抑制组成型COX - 1的非甾体抗炎药（NSAIDs）。罗非昔布含有甲砜成分，而塞来昔布和伐地昔布具有未取代的芳基磺酰胺部分。后一组是许多碳酸酐酶（CA）抑制剂所共有的。利用酶动力学和X射线晶体学，我们证明了COX - 2特异性芳基磺酰胺型的塞来昔布和伐地昔布对完全不相关的碳酸酐酶（CA）家族的同工酶，如CA I、II、IV和IX具有意想不到的纳摩尔亲和力，而罗非昔布甲砜型则没有作用。当口服给予青光眼兔时，塞来昔布和伐地昔布降低了眼压，表明这些药物可能对治疗这种疾病有用。塞来昔布与CA II复合物的晶体结构表明，这种抑制作用部分是通过磺酰胺基团与CA II的催化锌结合介导的。为了研究这些化合物在COX - 2和CA II之间交叉反应的结构基础，我们根据容纳药物分子不同部分的结合位点暴露氨基酸之间的局部物理化学相似性，比较了两种蛋白质结合口袋的分子识别特性。我们在Relibase中实施的方法Cavbase检测到了这些位点之间的相似性，表明有可能预测药物在功能不相关靶蛋白之间意想不到的交叉反应。观察到的与CA的交叉反应也可能导致药理学特征的差异，特别是在青光眼和抗癌治疗方面，并可能为这些COX - 2选择性NSAIDs带来新的机会。
