2. Academic Validation
  3. Discovery of potent indoleamine 2,3-dioxygenase (IDO) inhibitor from alkaloids in Picrasma quassioides by virtual screening and in vitro evaluation

Discovery of potent indoleamine 2,3-dioxygenase (IDO) inhibitor from alkaloids in Picrasma quassioides by virtual screening and in vitro evaluation

  • Fitoterapia. 2019 Mar:133:137-145. doi: 10.1016/j.fitote.2019.01.005.
Ning Wang 1,  Jie Zhang 1,  Qiao Li 1,  Hui Xu 2,  Geng Chen 3,  Zhiyong Li 4,  Difa Liu 5,  Xin Yang 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
  • 2 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China. Electronic address: xuhui@ytu.edu.cn.
  • 3 School of Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China.
  • 4 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China; State Key Laboratory of Natural Medicine and Traditional Chinese Medicine Injections, Jiangxi Qingfeng Pharmaceutical Co., Ltd., Ganzhou 341000, China.
  • 5 State Key Laboratory of Natural Medicine and Traditional Chinese Medicine Injections, Jiangxi Qingfeng Pharmaceutical Co., Ltd., Ganzhou 341000, China.
  • 6 School of Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China. Electronic address: yangx@ytu.edu.cn.
PMID: 30654128 DOI: 10.1016/j.fitote.2019.01.005
Abstract

Indoleamine 2,3-dioxygenase (IDO) is one of the important targets for Cancer Immunotherapy through tryptophan pathway. Recently it has being paid great attention to search potent and safe IDO Inhibitor from small-molecule compounds. Picrasma quassioides is a kind of medicinal plant abundant with tryptophan-derived Indole Alkaloids. By virtual screening and kinetic method for enzymatic analysis, lead compounds with potential IDO inhibitory activity were discovered for the first time from PQAs, the natural Alkaloids in Picrasma quassioides. The results based on molecular docking analysis and structure-activity relationship (SAR) study demonstrated that coordinating with ferrous ion on the active site of IDO has a great impact on the inhibition potency, and β-carboline with carboxyl substituted on C-1 is the key pharmacophore for IDO inhibition of PQAs. Enzymatic assay provided further evidence for the effectiveness of β-carboline-1-carboxylic acid, which displayed as the most potent competitive inhibitor of IDO among these PQAs, and is even more potent than the recognized positive control 1-methyl tryptophan. This natural tryptophan-derived alkaloid thus deserved further deep research as a promising IDO modulator for Cancer Immunotherapy.

Keywords

Enzyme kinetics; Indole alkaloids in Picrasma quassioides; Indoleamine 2,3-dioxygenase inhibitor; Structure-activity relationship; Virtual screening.

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