Identification of a Novel Core Structure of Apo-Ido1 Inhibitors Through Virtual Screening and Preliminary Hit Optimization

  • J Chem Inf Model. 2025 Sep 22;65(18):9723-9737. doi: 10.1021/acs.jcim.5c01041.
Yekui Yin  1  2  3 ,  Meiqi He  1  2  3 ,  Jianda Yue  1  2  3 ,  Yaqi Li  1  2  3 ,  Jiuxi Peng  1  2  3 ,  Xiao Luo  1  2  3 ,  Zhenyu Wang  1  2  3 ,  Xiao He  4 ,  Songping Liang  1  2  3 ,  Zhonghua Liu  1  2  3 ,  Ying Wang  1  2  3
Affiliations
  • 1. The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081 Hunan, China.
  • 2. Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha 410081 Hunan, China.
  • 3. Institute of Interdisciplinary Studies, Hunan Normal University, Changsha 410081 Hunan, China.
  • 4. Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
PMID: 40911340 DOI: 10.1021/acs.jcim.5c01041
Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme considered as a potential therapeutic target for neurodegenerative diseases and Cancer. However, the further development of traditional IDO1 inhibitors has been hindered by their limited clinical efficacy. Recently, type IV apo-IDO1 inhibitors offer a new strategy for developing IDO1 inhibitors due to their highly selective and durable inhibition. In this study, we developed a virtual screening (VS) workflow to identify novel apo-IDO1 inhibitors. A hit compound MQ-1 (IC50 = 1.29 μM) was identified by molecular docking and binding pose metadynamics (BPMD). Biological evaluations confirmed that MQ-1 selectively targets apo-IDO1 and disrupts heme binding. To optimize the structure of MQ-1, free energy landscape was constructed, and the dissociation mechanism was explored by random accelerated molecular dynamics and self-organizing maps. Finally, several MQ-1 analogs with improved inhibitory activity were discovered, such as MQ-1a (IC50 = 1.03 μM), MQ-1e (IC50 = 0.81 μM), and MQ-1n (IC50 = 0.29 μM). The established VS workflow effectively applied to IDO1 and can also be applied to similar targets. The novel apo-IDO1 inhibitor core structure provides a starting point for potential antitumor drug development.

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