biostudies-literatureYang GGuangdong Natural Science FoundationShenzhen Science and Technology Innovation CommissionNational Natural Science Foundation of ChinaNational Key Research and Development Program of China4751https://www.ebi.ac.uk/biostudies/studies/S-EPMC11084299biostudies-literatureUnknown25(9)Malaria is a severe disease that presents a significant threat to human health. As resistance to current drugs continues to increase, there is an urgent need for new antimalarial medications. Aminoacyl-tRNA synthetases (aaRSs) represent promising targets for drug development. In this study, we identified <i>Plasmodium falciparum</i> tyrosyl-tRNA synthetase (<i>Pf</i>TyrRS) as a potential target for antimalarial drug development through a comparative analysis of the amino acid sequences and three-dimensional structures of human and plasmodium TyrRS, with particular emphasis on differences in key amino acids at the aminoacylation site. A total of 2141 bioactive compounds were screened using a high-throughput thermal shift assay (TSA). Okanin, known as an inhibitor of LPS-induced TLR4 expression, exhibited potent inhibitory activity against <i>Pf</i>TyrRS, while showing limited inhibition of human TyrRS. Furthermore, bio-layer interferometry (BLI) confirmed the high affinity of okanin for <i>Pf</i>TyrRS. Molecular dynamics (MD) simulations highlighted the stable conformation of okanin within <i>Pf</i>TyrRS and its sustained binding to the enzyme. A molecular docking analysis revealed that okanin binds to both the tyrosine and partial ATP binding sites of the enzyme, preventing substrate binding. In addition, the compound inhibited the production of <i>Plasmodium falciparum</i> in the blood stage and had little cytotoxicity. Thus, okanin is a promising lead compound for the treatment of malaria caused by <i>P. falciparum</i>.International journal of molecular sciencesCompetitive Inhibition of Okanin against <i>Plasmodium falciparum</i> Tyrosyl-tRNA Synthetase.PMC110842992021YFC23001002021B151502004732271314JCYJ20200109142446804ZDSYS20230626091203007Weng QSun LYang GLi XLi ZQian YLiang YQin YYan YCheng YfalseCompetitive Inhibition of Okanin against <i>Plasmodium falciparum</i> Tyrosyl-tRNA Synthetase.Malaria is a severe disease that presents a significant threat to human health. As resistance to current drugs continues to increase, there is an urgent need for new antimalarial medications. Aminoacyl-tRNA synthetases (aaRSs) represent promising targets for drug development. In this study, we identified <i>Plasmodium falciparum</i> tyrosyl-tRNA synthetase (<i>Pf</i>TyrRS) as a potential target for antimalarial drug development through a comparative analysis of the amino acid sequences and three-dimensional structures of human and plasmodium TyrRS, with particular emphasis on differences in key amino acids at the aminoacylation site. A total of 2141 bioactive compounds were screened using a high-throughput thermal shift assay (TSA). Okanin, known as an inhibitor of LPS-induced TLR4 expression, exhibited potent inhibitory activity against <i>Pf</i>TyrRS, while showing limited inhibition of human TyrRS. Furthermore, bio-layer interferometry (BLI) confirmed the high affinity of okanin for <i>Pf</i>TyrRS. Molecular dynamics (MD) simulations highlighted the stable conformation of okanin within <i>Pf</i>TyrRS and its sustained binding to the enzyme. A molecular docking analysis revealed that okanin binds to both the tyrosine and partial ATP binding sites of the enzyme, preventing substrate binding. In addition, the compound inhibited the production of <i>Plasmodium falciparum</i> in the blood stage and had little cytotoxicity. Thus, okanin is a promising lead compound for the treatment of malaria caused by <i>P. falciparum</i>.2024-01-01T00:00:00Z2024 Apr2026-05-20T03:19:39.323Z2026-05-20T03:08:14.959ZS-EPMC110842993873197010.3390/ijms25094751