2. Academic Validation
  3. Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors

Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors

  • Eur J Med Chem. 2019 Dec 15:184:111750. doi: 10.1016/j.ejmech.2019.111750.
Yi Zou 1,  Yue Hu 2,  Shushan Ge 3,  Yingbo Zheng 3,  Yuezhen Li 4,  Wen Liu 2,  Wenjie Guo 5,  Yihua Zhang 3,  Qiang Xu 6,  Yisheng Lai 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, PR China; CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203, PR China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, PR China.
  • 3 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 4 Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, PR China. Electronic address: guowj@nju.edu.cn.
  • 6 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, PR China. Electronic address: molpharm@163.com.
  • 7 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: yslai@cpu.edu.cn.
PMID: 31610376 DOI: 10.1016/j.ejmech.2019.111750
Abstract

Developing small molecules occupying the heme-binding site using computational approaches remains a challenging task because it is difficult to characterize heme-ligand interaction in heme-containing protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular heme-containing dioxygenase which is associated with the immunosuppressive effects in Cancer. With IDO1 as an example, herein we report a combined virtual screening (VS) strategy including high-specificity heme-binding group (HmBG)-based pharmacophore screening and cascade molecular docking to identify novel IDO1 inhibitors. A total of four hit compounds were obtained and showed proper binding with the heme iron coordinating site. Further structural optimization led to a promising compound S18-3, which exerted potent anti-tumor efficacy in BALB/c mice bearing established CT26 tumors by activating the host's immune system. These results suggest that S18-3 merits further study to assess its potential for the intervention of Cancer. Furthermore, our study also unveils a novel in silico-based strategy for identifying potential regulators for hemeproteins within short timeframe.

Keywords

Cancer immunotherapy; Drug design; Heme; IDO1; Molecular dynamics simulation; T cell; Virtual screening.

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