Two-prong inhibitors for human carbonic anhydrase II.
Two-prong inhibitors for human carbonic anhydrase II.
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人碳酸酐酶 II 的双管齐下抑制剂。
DOI：
10.1021/ja047271k
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发表时间：
2004
影响因子：
15
通讯作者：
Srivastava,DK
中科院分区：
文献类型：
--
作者：
Roy,BidhanC;Banerjee,AbirL;Swanson,Michael;Jia,XiaoG;Haldar,ManasK;Mallik,Sanku;Srivastava,DK
酶抑制剂通常是通过考虑酶活性部位口袋的整体尺寸来设计的。这种传统的方法往往不能为它们的同源酶产生所需的抑制剂亲和力。为了规避这些限制，我们考虑通过连接锚链基团来增强抑制剂的结合亲和力，这些基团将与表面暴露的氨基酸残基相互作用。这一策略已被用于抑制人碳酸酐酶II。苯磺酰胺是该酶的弱抑制剂，但当它通过间隔基与亚氨基二乙酸酯−Cu2+(与表面暴露的His残基相互作用)连接时，其结合亲和力提高约2个数量级。这种“双管齐下”的方法有望成为将弱的酶抑制剂转化为紧密结合的抑制剂的一般策略。
The enzyme inhibitors are usually designed by taking into consideration the overall dimensions of the enzyme's active site pockets. This conventional approach often fails to produce desirable affinities of inhibitors for their cognate enzymes. To circumvent such constraints, we contemplated enhancing the binding affinities of inhibitors by attaching tether groups, which would interact with the surface exposed amino acid residues. This strategy has been tested for the inhibition of human carbonic anhydrase II. Benzenesulfonamide serves as a weak inhibitor for the enzyme, but when it is conjugated to iminodiacetate−Cu2+(which interacts with the surface-exposed His residues) via a spacer group, its binding affinity is enhanced by about 2 orders of magnitude. This “two-prong” approach is expected to serve as a general strategy for converting weak inhibitors of enzymes into tight-binding inhibitors.