Frontiers in Pharmacology (Mar 2018)

Discovery of Novel Inhibitors of Indoleamine 2,3-Dioxygenase 1 Through Structure-Based Virtual Screening

  • Guoqing Zhang,
  • Guoqing Zhang,
  • Jing Xing,
  • Jing Xing,
  • Yulan Wang,
  • Yulan Wang,
  • Lihao Wang,
  • Yan Ye,
  • Yan Ye,
  • Dong Lu,
  • Dong Lu,
  • Jihui Zhao,
  • Jihui Zhao,
  • Xiaomin Luo,
  • Mingyue Zheng,
  • Shiying Yan

DOI
https://doi.org/10.3389/fphar.2018.00277
Journal volume & issue
Vol. 9

Abstract

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Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular monomeric heme-containing enzyme that catalyzes the first and the rate limiting step in catabolism of tryptophan via the kynurenine (KYN) pathway, which plays a significant role in the proliferation and differentiation of T cells. IDO1 has been proven to be an attractive target for anticancer therapy and chronic viral infections. In the present study, a class of IDO1 inhibitors with novel scaffolds were identified by virtual screening and biochemical validation, in which the compound DC-I028 shows moderate IDO1 inhibitory activity with an IC50 of 21.61 μM on enzymatic level and 89.11 μM on HeLa cell. In the following hit expansion stage, DC-I02806, an analog of DC-I028, showed better inhibitory activity with IC50 about 18 μM on both enzymatic level and cellular level. The structure–activity relationship (SAR) of DC-I028 and its analogs was then discussed based on the molecular docking result. The novel IDO1 inhibitors of DC-I028 and its analogs may provide useful clues for IDO1 inhibitor development.

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