Röhrig Ute F, Zoete Vincent, Michielin Olivier
Molecular Modeling Group, SIB Swiss Institute of Bioinformatics , 1015 Lausanne, Switzerland.
Department of Fundamental Oncology, Ludwig Lausanne Branch, University of Lausanne , 1066 Epalinges, Switzerland.
Biochemistry. 2017 Aug 22;56(33):4323-4325. doi: 10.1021/acs.biochem.7b00586. Epub 2017 Jul 27.
Indoleamine 2,3-dioxygenase 1 (IDO1) is an important target in cancer immunotherapy. The most advanced clinical compound, epacadostat (INCB024360), binds to the heme cofactor of IDO1 through an N-hydroxyamidine function. Conflicting binding modes have recently been proposed, reporting iron binding either through the hydroxyamidine oxygen or through the hydroxyamidine nitrogen atom. Here, we use quantum chemical calculations, docking, and quantum mechanics/molecular mechanics calculations based on available X-ray data to resolve this issue and to propose a physically meaningful binding mode. Our findings will aid the design of novel IDO1 ligands based on this pharmacophore.
吲哚胺2,3-双加氧酶1（IDO1）是癌症免疫治疗中的一个重要靶点。最先进的临床化合物依帕卡托（INCB024360）通过N-羟基脒官能团与IDO1的血红素辅因子结合。最近提出了相互矛盾的结合模式，报道铁通过羟基脒氧或通过羟基脒氮原子结合。在这里，我们使用量子化学计算、对接以及基于可用X射线数据的量子力学/分子力学计算来解决这个问题，并提出一种具有物理意义的结合模式。我们的研究结果将有助于基于这种药效团设计新型IDO1配体。
