Molecular Modeling Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
Laboratory of Glycochemistry and Asymmetric Synthesis, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
J Med Chem. 2021 Feb 25;64(4):2205-2227. doi: 10.1021/acs.jmedchem.0c01968. Epub 2021 Feb 8.
The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.
血红素酶吲哚胺 2,3-双加氧酶 1（IDO1）通过催化色氨酸代谢中犬尿氨酸途径的限速步骤，在免疫、神经元功能和衰老中发挥重要作用。已经开发出许多具有不同化学类型的 IDO1 抑制剂，主要用于癌症免疫治疗。由于血红素配体相互作用的显著选择性和敏感性，直接结合血红素铁的抑制剂的先导优化证明具有挑战性。在这里，我们提供了一组密切相关的小唑类化合物的实验数据，这些化合物的抑制活性差异超过 4 个数量级，范围从毫摩尔到纳摩尔水平。我们根据结构数据、分子动力学模拟和密度泛函理论计算来研究和合理化它们的活性。我们的结果不仅通过另外两种支架扩展了目前已知的四个具有亚微米级血红素结合 IDO1 抑制剂的确认化学类型，而且还提供了一种预测新型支架活性的模型。
