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

: 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.