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Design of Isoform-Selective Enzyme Inhibitors by Exploring Pocket Size According to the Lock-and-Key Principle
Biophysical Journal ( IF 3.4 ) Pub Date : 2020-10-01 , DOI: 10.1016/j.bpj.2020.08.037
Virginija Dudutienė 1 , Asta Zubrienė 1 , Visvaldas Kairys 2 , Alexey Smirnov 1 , Joana Smirnovienė 1 , Janis Leitans 3 , Andris Kazaks 3 , Kaspars Tars 3 , Lena Manakova 4 , Saulius Gražulis 4 , Daumantas Matulis 1
Affiliation  

In the design of high-affinity and enzyme isoform-selective inhibitors, we applied an approach of augmenting the substituents attached to the benzenesulfonamide scaffold in three ways, namely, substitutions at the 3,5- or 2,4,6-positions or expansion of the condensed ring system. The increased size of the substituents determined the spatial limitations of the active sites of the 12 catalytically active human carbonic anhydrase (CA) isoforms until no binding was observed because of the inability of the compounds to fit in the active site. This approach led to the discovery of high-affinity and high-selectivity compounds for the anticancer target CA IX and antiobesity target CA VB. The x-ray crystallographic structures of compounds bound to CA IX showed the positions of the bound compounds, whereas computational modeling confirmed that steric clashes prevent the binding of these compounds to other isoforms and thus avoid undesired side effects. Such an approach, based on the Lock-and-Key principle, could be used for the development of enzyme-specific drug candidate compounds.

中文翻译:

根据Lock-and-Key原理探索口袋大小设计异构体选择性酶抑制剂

在设计高亲和力和酶异构体选择性抑制剂时,我们采用了一种方法,以三种方式增加苯磺酰胺支架上的取代基,即 3,5-或 2,4,6-位的取代或扩展稠环系统。取代基大小的增加决定了 12 种具有催化活性的人碳酸酐酶 (CA) 异构体的活性位点的空间限制,直到由于化合物无法适应活性位点而未观察到结合。这种方法导致发现了抗癌靶标 CA IX 和抗肥胖靶标 CA VB 的高亲和力和高选择性化合物。与 CA IX 结合的化合物的 X 射线晶体结构显示了结合化合物的位置,而计算模型证实,空间冲突阻止了这些化合物与其他同种型的结合,从而避免了不想要的副作用。这种基于 Lock-and-Key 原理的方法可用于开发酶特异性候选药物化合物。
更新日期:2020-10-01
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