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Biochemistry. 2017 Aug 22;56(33):4323-4325. doi: 10.1021/acs.biochem.7b00586. Epub 2017 Jul 27.

The Binding Mode of N-Hydroxyamidines to Indoleamine 2,3-Dioxygenase 1 (IDO1).

Author information

1
Molecular Modeling Group, SIB Swiss Institute of Bioinformatics , 1015 Lausanne, Switzerland.
2
Department of Fundamental Oncology, Ludwig Lausanne Branch, University of Lausanne , 1066 Epalinges, Switzerland.
3
Department of Oncology, University of Lausanne and Centre Hospitalier Universitaire Vaudois (CHUV) , 1011 Lausanne, Switzerland.

Abstract

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.

PMID:
28731684
DOI:
10.1021/acs.biochem.7b00586
[Indexed for MEDLINE]

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