Esmaeili Sajjad, Ashrafi-Kooshk Mohammad Reza, Adibi Hadi, Khodarahmi Reza
Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Chem Biol Interact. 2017 Mar 1;265:24-35. doi: 10.1016/j.cbi.2017.01.014. Epub 2017 Jan 23.
The inhibitory activity of captopril, a thiol-containing competitive inhibitor of the angiotensin-converting enzyme, ACE, against esterase activity of carbonic anhydrase, CA was investigated. This small molecule, as well as enalapril, was selected in order to represents both thiol and carboxylate, as two well-known metal binding functional groups of metalloprotein inhibitors. Since captopril, has also been observed to inhibit other metalloenzymes such as tyrosinase and metallo-beta lactamase through binding to the catalytic metal ions and regarding CA as a zinc-containing metallo-enzyme, in the current study, we set out to determine whether captopril/enalapril inhibit CA esterase activity of the purified human CA II or not? Then, we revealed the inhibitors' potencies (IC, K and K values) and also mode of inhibition. Our results also showed that enalapril is more potent CA inhibitor than captopril. Since enalapril represents no sulfhydryl moiety, thus carboxylate group may have a determinant role in inhibiting of CA esterase activity, the conclusion confirmed by molecular docking studies. Additionally, since CA inhibitory potencies of captopril/enalapril were much lower than those of classic sulfonamide drugs, the findings of the current study may explain why these drugs exhibit no effective CA inhibition at the concentrations reached in vivo and also may shed light on the way of generating new class of inhibitors that will discriminately inhibit various CA isoforms.
研究了含硫醇的血管紧张素转换酶（ACE）竞争性抑制剂卡托普利对碳酸酐酶（CA）酯酶活性的抑制作用。选择这种小分子以及依那普利，是为了代表硫醇和羧酸盐这两种金属蛋白抑制剂中著名的金属结合官能团。由于卡托普利也被观察到通过与催化金属离子结合来抑制其他金属酶，如酪氨酸酶和金属β-内酰胺酶，并且鉴于CA是一种含锌金属酶，在本研究中，我们着手确定卡托普利/依那普利是否抑制纯化的人CA II的CA酯酶活性？然后，我们揭示了抑制剂的效力（IC、K和K值）以及抑制模式。我们的结果还表明，依那普利是比卡托普利更有效的CA抑制剂。由于依那普利没有巯基部分，因此羧基基团可能在抑制CA酯酶活性中起决定性作用，分子对接研究证实了这一结论。此外，由于卡托普利/依那普利的CA抑制效力远低于经典磺胺类药物，本研究的结果可能解释了为什么这些药物在体内达到的浓度下没有有效的CA抑制作用，也可能为开发能够选择性抑制各种CA同工型的新型抑制剂指明方向。
