Human indoleamine-2,3-dioxygenase 2 cofactor lability and low substrate affinity explained by homology modeling, molecular dynamics and molecular docking

Research output: Contribution to journalArticlepeer-review

11 Downloads (Pure)

Abstract

The human indoleamine-2,3-dioxygenase 2 (hIDO2) protein is growing of interest as it is increasingly implicated in multiple diseases (cancer, autoimmune diseases, COVID-19). However, it is only poorly reported in the literature. Its mode of action remains unknown because it does not seem to catalyze the reaction for which it is attributed: the degradation of the L-Tryptophan into N-formyl-kynurenine. This contrasts with its paralog, the human indoleamine-2,3-dioxygenase 1 (hIDO1), which has been extensively studied in the literature and for which several inhibitors are already in clinical trials. Yet, the recent failure of one of the most advanced hIDO1 inhibitors, the Epacadostat, could be caused by a still unknown interaction between hIDO1 and hIDO2. In order to better understand the mechanism of hIDO2, and in the absence of experimental structural data, a computational study mixing homology modeling, Molecular Dynamics, and molecular docking was conducted. The present article highlights an exacerbated lability of the cofactor as well as an inadequate positioning of the substrate in the active site of hIDO2, which might bring part of an answer to its lack of activity. Communicated by Ramaswamy H. Sarma.

Original languageEnglish
JournalJournal of biomolecular structure and dynamics
DOIs
Publication statusPublished - 2023

Keywords

  • dioxygenase
  • hIDO2
  • Homology modeling
  • L-Tryptophan
  • molecular docking
  • molecular dynamic

Fingerprint

Dive into the research topics of 'Human indoleamine-2,3-dioxygenase 2 cofactor lability and low substrate affinity explained by homology modeling, molecular dynamics and molecular docking'. Together they form a unique fingerprint.

Cite this