Structural analysis of inhibitor binding to human carbonic anhydrase II
Structural analysis of inhibitor binding to human carbonic anhydrase II
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DOI：
10.1002/pro.5560071201
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发表时间：
1998-12-01
期刊：
影响因子：
8
通讯作者：
Christianson, DW
中科院分区：
文献类型：
--
作者：
Boriack-Sjodin, PA;Zeitlin, S;Christianson, DW
碳酸酐酶II（CAII）与磺胺类抑制剂复合的X射线晶体结构阐明了纳摩尔范围内高亲和力结合的结构决定因素。主要的结合相互作用是主要的磺酰胺基团与活性位点锌离子的配位。次级相互作用微调了活性位点空腔区域中距离锌>5埃的紧密结合，并且这项工作突出了三个这样的特征：（1）与单环2，5-噻吩二磺酰胺骨架相比，双环噻吩并噻嗪-6-磺酰胺-1，1-二氧化物抑制剂骨架的有利构象限制：（2）连接到仲磺酰胺基团上的最佳取代基，其靶向与由Phe 131、Leu 198和Pro202定义的疏水补丁相互作用;（3）双环噻吩并噻嗪-6-磺酰胺C-4位的最佳立体化学和构型，C-4位取代基可与催化质子穿梭剂His 64相互作用。结构-活性关系使布林佐胺（Azopt（TM））开发过程中观察到的亲和力趋势合理化，布林佐胺是批准用于治疗青光眼的最新碳酸酐酶抑制剂。
X-ray crystal structures of carbonic anhydrase II (CAII) complexed with sulfonamide inhibitors illuminate the structural determinants of high affinity binding in the nanomolar regime. The primary binding interaction is the coordination of a primary sulfonamide group to the active site zinc ion. Secondary interactions fine-tune tight binding in regions of the active site cavity >5 Angstrom away from zinc, and this work highlights three such features: (1) advantageous conformational restraints of a bicyclic thienothiazene-6-sulfonamide- 1,1-dioxide inhibitor skeleton in comparison with a monocyclic 2,5-thiophenedisulfonamide skeleton: (2) optimal substituents attached to a secondary sulfonamide group targeted to interact with hydrophobic patches defined by Phe131, Leu198, and Pro202; and (3) optimal stereochemistry and configuration at the C-4 position of bicyclic thienothiazene-6-sulfonamides; the C-4 substituent can interact with His64, the catalytic proton shuttle. Structure-activity relationships rationalize affinity trends observed during the development of brinzolamide (Azopt(TM)), the newest carbonic anhydrase inhibitor approved for the treatment of glaucoma.