PMID- 31610376
OWN - NLM
STAT- MEDLINE
DCOM- 20200218
LR  - 20211108
IS  - 1768-3254 (Electronic)
IS  - 0223-5234 (Linking)
VI  - 184
DP  - 2019 Dec 15
TI  - Effective Virtual Screening Strategy toward heme-containing proteins: 
      Identification of novel IDO1 inhibitors.
PG  - 111750
LID - S0223-5234(19)30902-X [pii]
LID - 10.1016/j.ejmech.2019.111750 [doi]
AB  - 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.
CI  - Copyright (c) 2019 Elsevier Masson SAS. All rights reserved.
FAU - Zou, Yi
AU  - Zou Y
AD  - 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.
FAU - Hu, Yue
AU  - Hu Y
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing, 210093, PR China.
FAU - Ge, Shushan
AU  - Ge S
AD  - 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.
FAU - Zheng, Yingbo
AU  - Zheng Y
AD  - 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.
FAU - Li, Yuezhen
AU  - Li Y
AD  - Department of Organic Chemistry, School of Science, China Pharmaceutical 
      University, Nanjing, 211198, PR China.
FAU - Liu, Wen
AU  - Liu W
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing, 210093, PR China.
FAU - Guo, Wenjie
AU  - Guo W
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing, 210093, PR China. Electronic address: 
      guowj@nju.edu.cn.
FAU - Zhang, Yihua
AU  - Zhang Y
AD  - 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.
FAU - Xu, Qiang
AU  - Xu Q
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Nanjing, 210093, PR China. Electronic address: 
      molpharm@163.com.
FAU - Lai, Yisheng
AU  - Lai Y
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20191003
PL  - France
TA  - Eur J Med Chem
JT  - European journal of medicinal chemistry
JID - 0420510
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hydrazines)
RN  - 0 (IDO1 protein, human)
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Cell Proliferation/drug effects
MH  - Colonic Neoplasms/*drug therapy/metabolism/pathology
MH  - Dose-Response Relationship, Drug
MH  - Drug Evaluation, Preclinical
MH  - Drug Screening Assays, Antitumor
MH  - HeLa Cells
MH  - Humans
MH  - Hydrazines/chemical synthesis/chemistry/*pharmacology
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase/*antagonists & inhibitors/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Molecular Structure
MH  - Structure-Activity Relationship
MH  - Tumor Cells, Cultured
OTO - NOTNLM
OT  - Cancer immunotherapy
OT  - Drug design
OT  - Heme
OT  - IDO1
OT  - Molecular dynamics simulation
OT  - T cell
OT  - Virtual screening
EDAT- 2019/10/15 06:00
MHDA- 2020/02/19 06:00
CRDT- 2019/10/15 06:00
PHST- 2019/06/12 00:00 [received]
PHST- 2019/09/22 00:00 [revised]
PHST- 2019/09/28 00:00 [accepted]
PHST- 2019/10/15 06:00 [pubmed]
PHST- 2020/02/19 06:00 [medline]
PHST- 2019/10/15 06:00 [entrez]
AID - S0223-5234(19)30902-X [pii]
AID - 10.1016/j.ejmech.2019.111750 [doi]
PST - ppublish
SO  - Eur J Med Chem. 2019 Dec 15;184:111750. doi: 10.1016/j.ejmech.2019.111750. Epub 
      2019 Oct 3.