Pantouris Georgios, Loudon-Griffiths James, Mowat Christopher G
a EaStCHEM School of Chemistry, University of Edinburgh , Edinburgh , UK.
J Enzyme Inhib Med Chem. 2016;31(sup1):70-78. doi: 10.3109/14756366.2016.1170013. Epub 2016 Apr 20.
Tryptophan 2,3-dioxygenase (TDO) is a cytosolic protein with a proven immunomodulatory function that promotes tumoral immune resistance and proliferation. Despite the interest in TDO as a therapeutic target in cancer treatment, the number of biologically useful inhibitors is limited. Herein, we report isatin derivatives as a new class of TDO inhibitors. Through structure-activity relationships and molecular docking studies, we optimized the inhibition potency of isatin derivatives by >130-fold and elucidated the mechanistic details that control their mode of action. Hydrogen bond interactions between the compound and key active site residues of TDO, freedom upon rotation of the C3 chemical moiety and the presence of chlorines in the benzene ring of the compound comprise the properties that an isatin-based inhibitor requires to effectively inhibit the enzymatic activity of TDO.
色氨酸2,3-双加氧酶（TDO）是一种具有免疫调节功能的胞质蛋白，可促进肿瘤免疫抵抗和增殖。尽管TDO作为癌症治疗的治疗靶点备受关注，但具有生物学活性的抑制剂数量有限。在此，我们报道异吲哚酮衍生物是一类新型的TDO抑制剂。通过构效关系和分子对接研究，我们将异吲哚酮衍生物的抑制效力提高了130倍以上，并阐明了控制其作用模式的机制细节。化合物与TDO关键活性位点残基之间的氢键相互作用、C3化学基团旋转的自由度以及化合物苯环中氯的存在构成了基于异吲哚酮的抑制剂有效抑制TDO酶活性所需的特性。
