Mycobacterial carbonic anhydrase inhibition with phenolic acids and esters: kinetic and computational investigations
Mycobacterial carbonic anhydrase inhibition with phenolic acids and esters: kinetic and computational investigations
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DOI：
10.1039/c6ob01477a
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发表时间：
2016-09-21
影响因子：
3.2
通讯作者：
Botta, Maurizio
中科院分区：
文献类型：
--
作者：
Cau, Ylenia;Mori, Mattia;Botta, Maurizio
研究了一系列酚酸及其酯类化合物咖啡酸、阿魏酸和对香豆酸的衍生物对结核分枝杆菌Rv1248、Rv3588和Rv3273β-CaS三种β-碳酸氢酶(Cas，EC 4.2.1.1)的抑制作用。其中一些化合物是致病酶的低微摩尔抑制剂，它们对人类广泛存在的胞浆异构体CA I和CA II没有抑制活性。用计算方法研究了这些抑制剂与两种细菌酶的结合方式。我们认为，抑制剂从CA活性中心锚定到锌配位的水分子上，从而干扰了氢氧化锌对底物二氧化碳的亲核攻击。这些化合物可能被认为是有趣的抗分枝杆菌先导化合物。
A series of phenolic acids and some of their esters, derivatives of caffeic, ferulic, and p-coumaric acid, was investigated for the inhibition of three beta-carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic bacterium Mycobacterium tuberculosis, Rv1248, Rv3588 and Rv3273 beta-CAs. Some of these compounds were low micromolar inhibitors of the pathogenic enzymes and they did not show inhibitory activity against the human widespread cytosolic isoforms CA I and II. The binding mode of these inhibitors to two of the bacterial enzymes was investigated by computational approaches. We propose that the inhibitors anchor to the zinc-coordinated water molecule from the CA active site interfering with the nucteophilic attack of the zinc hydroxide on the substrate CO2. These compounds may be considered as interesting anti-mycobacterial lead compounds.