Coptisine, a natural alkaloid from Coptidis Rhizoma, inhibits plasmodium falciparum dihydroorotate dehydrogenase

Li Lang; Qian Hu; Jingyuan Wang; Zehui Liu; Jin Huang; Weiqiang Lu; Ying Huang

doi:10.1111/cbdd.13197

Coptisine, a natural alkaloid from Coptidis Rhizoma, inhibits plasmodium falciparum dihydroorotate dehydrogenase

Chem Biol Drug Des. 2018 Jul;92(1):1324-1332. doi: 10.1111/cbdd.13197. Epub 2018 May 12.

Authors

Li Lang¹, Qian Hu¹, Jingyuan Wang¹, Zehui Liu¹, Jin Huang¹, Weiqiang Lu², Ying Huang³

Affiliations

¹ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
² Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
³ Guangdong Institute for Drug Control, Guangzhou, Guangdong, China.

PMID: 29582555
DOI: 10.1111/cbdd.13197

Abstract

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is a promising drug target for antimalarial chemotherapy. In our continuous efforts to develop more potent PfDHODH inhibitors, a unique library of active ingredients from traditional Chinese medicine (TCM) has been collected and was screened in this study. Through the initial screening, we found that coptisine, a natural alkaloid from TCM Coptidis Rhizoma, was a novel and potent inhibitor of PfDHODH with an IC₅₀ value of 1.83 ± 0.08 μm. At the same time, enzyme kinetic analysis using Lineweaver-Burk plot indicated that coptisine is an uncompetitive inhibitor for PfDHODH. Thermal shift assay and molecular docking simulation research reveal that coptisine is capable of binding with PfDHODH. Moreover, coptisine exhibits weak inhibition activity against human DHODH, indicating that coptisine is a selective inhibitor of PfDHODH. Taken together, our study highlights the potential of active ingredients in TCM as valuable resource for discovering novel chemical scaffolds for PfDHODH.

Keywords: coptisine; dihydroorotate dehydrogenase; plasmodium falciparum; pyrimidine biosynthesis; traditional Chinese medicine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkaloids / chemistry*
Alkaloids / metabolism
Alkaloids / pharmacology
Berberine / analogs & derivatives*
Berberine / chemistry
Berberine / metabolism
Berberine / pharmacology
Binding Sites
Catalytic Domain
Coptis / chemistry*
Coptis / metabolism
Dihydroorotate Dehydrogenase
Drugs, Chinese Herbal / chemistry
Drugs, Chinese Herbal / metabolism
Drugs, Chinese Herbal / pharmacology
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Humans
Hydrogen Bonding
Kinetics
Molecular Docking Simulation
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors
Oxidoreductases Acting on CH-CH Group Donors / genetics
Oxidoreductases Acting on CH-CH Group Donors / metabolism*
Plasmodium falciparum / drug effects
Plasmodium falciparum / enzymology
Protozoan Proteins / antagonists & inhibitors
Protozoan Proteins / genetics
Protozoan Proteins / metabolism*
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / isolation & purification

Substances

Alkaloids
Dihydroorotate Dehydrogenase
Drugs, Chinese Herbal
Enzyme Inhibitors
Protozoan Proteins
Recombinant Proteins
coptisine
Berberine
Oxidoreductases Acting on CH-CH Group Donors