Carbonic anhydrase inhibitors: X-ray and molecular modeling study for the interaction of a fluorescent antitumor sulfonamide with isozyme II and IX
Carbonic anhydrase inhibitors: X-ray and molecular modeling study for the interaction of a fluorescent antitumor sulfonamide with isozyme II and IX
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DOI：
10.1021/ja061574s
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发表时间：
2006-06-28
影响因子：
15
通讯作者：
Supuran, Claudiu T.
中科院分区：
文献类型：
--
作者：
Alterio, Vincenzo;Vitale, Rosa Maria;Supuran, Claudiu T.
报道了荧光抗肿瘤磺酰胺碳酸酐酶（CA，EC，4.2.1.1）抑制剂（4-氨磺酰苯乙基）硫脲基荧光素（1）与胞质异构体hCA II复合的X射线晶体结构，以及1与肿瘤相关异构体hCA IX的加合物的模型研究。它与hCA II的结合类似于其他苯磺酰胺，离子化的磺酰胺与酶活性位点内的Zn 2+离子配位，并且还参与与残基Thr 199和Glu 106的氢键网络。1的支架没有在酶活性位点内建立极性相互作用，但与Gln 92、Val 121、Phe 131、Val 135、Leu 198、Thr 199、Thr 200和Pro 202形成疏水接触（< 4.5埃）。取代的3-羧基-氨基-苯基官能团与Phe 131、Gly 132和Val 135的范德华距离为货车。大体积的三环荧光素部分位于活性位点的边缘，在蛋白质表面上，并与残基Asp 130-Val 135形成的α-螺旋强烈相互作用。所有这些相互作用都保留在hCA IX-1加合物中，但1的荧光素尾的羰基部分参与与Arg 130的胍部分的强氢键，Arg 130是hCA IX活性位点的氨基酸特征。这可以解释1对hCA IX的亲和力比hCA II高大约2倍，并且可以解释为什么该化合物在体内仅在过表达CA IX的缺氧肿瘤中特异性积累，而不在正常组织中积累。该化合物正在临床研究中作为急性缺氧肿瘤的成像工具。
The X-ray crystal structure of the fluorescent antitumor sulfonamide carbonic anhydrase (CA, EC, 4.2.1.1) inhibitor (4-sulfamoylphenylethyl) thioureido fluorescein (1) in complex with the cytosolic isoform hCA II is reported, together with a modeling study of the adduct of 1 with the tumor-associated isoform hCA IX. Its binding to hCA II is similar to that of other benzesulfonamides, with the ionized sulfonamide coordinated to the Zn2+ ion within the enzyme active site, and also participating in a network of hydrogen bonds with residues Thr199 and Glu106. The scaffold of 1 did not establish polar interactions within the enzyme active site but made hydrophobic contacts ( < 4.5 angstrom) with Gln92, Val121, Phe131, Val135, Leu198, Thr199, Thr200, and Pro202. The substituted 3-carboxy-amino-phenyl functionality was at van der Waals distance from Phe131, Gly132, and Val135. The bulky tricyclic fluorescein moiety was located at the rim of the active site, on the protein surface, and strongly interacted with the alpha-helix formed by residues Asp130-Val135. All these interactions were preserved in the hCA IX-1 adduct, but the carbonyl moiety of the fluorescein tail of 1 participates in a strong hydrogen bond with the guanidine moiety of Arg130, an amino acid characteristic of the hCA IX active site. This may account for the roughly 2 times higher affinity of 1 for hCA IX over hCA II and may explain why in vivo the compound specifically accumulates only in hypoxic tumors overexpressing CA IX and not in the normal tissues. The compound is in clinical studies as an imaging tool for acute hypoxic tumors.