Tanpure Rajendra P, Ren Bin, Peat Thomas S, Bornaghi Laurent F, Vullo Daniela, Supuran Claudiu T, Poulsen Sally-Ann
Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
J Med Chem. 2015 Feb 12;58(3):1494-501. doi: 10.1021/jm501798g. Epub 2015 Jan 27.
We present a new approach to carbonic anhydrase II (CA II) inhibitor design that enables close interrogation of the regions of the CA active site where there is the greatest variability in amino acid residues among the different CA isozymes. By appending dual tail groups onto the par excellence CA inhibitor acetazolamide, compounds that may interact with the distinct hydrophobic and hydrophilic halves of the CA II active site were prepared. The dual-tail combinations selected included (i) two hydrophobic moieties, (ii) two hydrophilic moieties, and (iii) one hydrophobic and one hydrophilic moiety. The CA enzyme inhibition profile as well as the protein X-ray crystal structure of compound 3, comprising one hydrophobic and one hydrophilic tail moiety, in complex with CA II is described. This novel dual-tail approach has provided an enhanced opportunity to more fully exploit interactions with the CA active site by enabling these molecules to interact with the distinct halves of the active site. In addition to the dual-tail compounds, a corresponding set of single-tail derivatives was synthesized, enabling a comparative analysis of the single-tail versus dual-tail compound CA inhibition profile.
我们提出了一种设计碳酸酐酶II（CA II）抑制剂的新方法，该方法能够深入研究CA活性位点中不同CA同工酶氨基酸残基差异最大的区域。通过在堪称典范的CA抑制剂乙酰唑胺上连接双尾基团，制备了可能与CA II活性位点不同疏水和亲水部分相互作用的化合物。所选择的双尾组合包括：（i）两个疏水部分，（ii）两个亲水部分，以及（iii）一个疏水部分和一个亲水部分。描述了包含一个疏水尾部分和一个亲水尾部分的化合物3与CA II复合物的CA酶抑制谱以及蛋白质X射线晶体结构。这种新颖的双尾方法提供了一个更好的机会，通过使这些分子与活性位点的不同部分相互作用，更充分地利用与CA活性位点的相互作用。除了双尾化合物外，还合成了相应的单尾衍生物，从而能够对单尾和双尾化合物的CA抑制谱进行比较分析。
