Inhibition Mechanisms of Indoleamine 2,3-Dioxygenase 1 (IDO1)

Indoleamine 2,3-dioxygenase 1 (IDO1)
catalyzes the rate-limiting
step in the kynurenine pathway of tryptophan metabolism, which is
involved in immunity, neuronal function, and aging. Its implication
in pathologies such as cancer and neurodegenerative diseases has stimulated
the development of IDO1 inhibitors. However, negative phase III clinical
trial results of the IDO1 inhibitor epacadostat in cancer immunotherapy
call for a better understanding of the role and the mechanisms of
IDO1 inhibition. In this work, we investigate the molecular inhibition
mechanisms of four known IDO1 inhibitors and of two quinones in detail,
using different experimental and computational approaches. We also
determine for the first time the X-ray structure of the highly efficient
1,2,3-triazole inhibitor MMG-0358. Based on our results and a comprehensive
literature overview, we propose a classification scheme for IDO1 inhibitors
according to their inhibition mechanism, which will be useful for
further developments in the field.