Discovery of novel IDO1 inhibitors via structure-based virtual screening and biological assays

Huizhen Ge, Longfei Mao, Jie Zhao, Yuwei Wang, Danfeng Shi, Xing Yang, Xiaorui Wang, Huanxiang Liu, Xiaojun Yao

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the first and rate-limiting step in catabolism of tryptophan via the kynurenine pathway, which plays a pivotal role in the proliferation and differentiation of T cells. IDO1 has been proven to be an attractive target for many diseases, such as breast cancer, lung cancer, colon cancer, prostate cancer, etc. In this study, docking-based virtual screening and bioassays were conducted to identify novel inhibitors of IDO1. The cellular assay demonstrated that 24 compounds exhibited potent inhibitory activity against IDO1 at micromolar level, including 8 compounds with IC50 values below 10 μM and the most potent one (compound 1) with IC50 of 1.18 ± 0.04 μM. Further lead optimization based on similarity searching strategy led to the discovery of compound 28 as an excellent inhibitor with IC50 of 0.27 ± 0.02 μM. Then, the structure–activity relationship of compounds 1, 2, 8 and 14 analogues is discussed. The interaction modes of two compounds against IDO1 were further explored through a Python Based Metal Center Parameter Builder ( molecular dynamics simulation, binding free energy calculation and electrostatic potential analysis. The novel IDO1 inhibitors of compound 1 and its analogues could be considered as promising scaffold for further development of IDO1 inhibitors.

Original languageEnglish
Pages (from-to)679-694
Number of pages16
JournalJournal of Computer-Aided Molecular Design
Issue number5
Publication statusPublished - May 2021
Externally publishedYes


  • IDO1 inhibitor
  • MM-GBSA calculation
  • Molecular docking
  • Molecular dynamics simulations
  • Virtual screening


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