Shi Baolu, Stevenson Ross, Campopiano Dominic J, Greaney Michael F
School of Chemistry, University of Edinburgh, The King's Buildings, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
J Am Chem Soc. 2006 Jul 5;128(26):8459-67. doi: 10.1021/ja058049y.
Protein-directed dynamic combinatorial chemistry (DCC) relies on reversible chemical reactions that can function under the near-physiological conditions required by the biological target. Few classes of reaction have so far proven effective at generating dynamic combinatorial libraries (DCLs) under such constraints. In this study, we establish the conjugate addition of thiols to enones as a reaction well-suited for the synthesis of dynamic combinatorial libraries (DCLs) directed by the active site of the enzyme glutathione S-transferase (GST). The reaction is fast, freely reversible at basic pH, and easily interfaced with the protein, which is a target for the design of inhibitors in cancer therapy and the treatment of parasitic diseases such as schistosomiasis. We have synthesized DCLs based on glutathione (GSH, 1) and the enone ethacrynic acid, 2a. By varying either set of components, we can choose to probe either the GSH binding region ("G site") or the adjacent hydrophobic acceptor binding region ("H site") of the GST active site. In both cases the strongest binding DCL components are identified due to molecular amplification by GST which, in the latter system, leads to the identification of two new inhibitors for the GST enzyme.
蛋白质导向的动态组合化学（DCC）依赖于可逆化学反应，这些反应能够在生物靶标所需的近生理条件下发挥作用。到目前为止，很少有几类反应在这种限制条件下能有效生成动态组合库（DCL）。在本研究中，我们确立了硫醇与烯酮的共轭加成反应，该反应非常适合用于合成由谷胱甘肽S-转移酶（GST）活性位点导向的动态组合库（DCL）。该反应速度快，在碱性pH条件下可自由可逆，并且能轻松与蛋白质结合，而蛋白质是癌症治疗和血吸虫病等寄生虫病抑制剂设计的靶点。我们基于谷胱甘肽（GSH，1）和烯酮依他尼酸（2a）合成了DCL。通过改变任何一组组分，我们可以选择探测GST活性位点的谷胱甘肽结合区域（“G位点”）或相邻的疏水受体结合区域（“H位点”）。在这两种情况下，由于GST的分子扩增作用，都能鉴定出结合最强的DCL组分，在后一种体系中，这导致鉴定出两种新的GST酶抑制剂。
