Wirdatun Nafisah, Gusnia Meilin Gholam, Riyan Alifbi Putera Irsal, Maheswari Alfira Dwicesaria, Elma Sakinatus Sajidah, Fatima Shahid, Fachrur Rizal Mahendra, David Herawan, Rahmah Muthmainnah Azam
Malaria remains a primary global health concern, and targeting proteins from the calcium-dependent protein kinase (CDPK) family of Plasmodium falciparum represents a novel and promising therapeutic strategy. In this study, we investigated the molecular interactions between sea buckthorn-derived compounds and P. falciparum CDPK3 and CDPK4 to address the unexplored antimalarial potential of this traditionally used medicinal plant. The active sites of each CDPK protein were predicted to facilitate docking analysis. In silico assessments of absorption, distribution, metabolism, and excretion (ADME), along with PASS, were used to evaluate drug-likeness properties and antiprotozoal potential. Density functional theory (DFT) calculations were performed to predict the electronic reactivity of potential inhibitors, and molecular dynamics (MD) simulations were used to evaluate complex stability. The results showed that the active sites of CDPK3 and CDPK4 were successfully identified, with 39 amino acid residues for CDPK3 and 105 for CDPK4. Molecular docking analyses demonstrated favorable binding affinities, ranging from 4.026 to 8.917 kcal/mol for the CDPK3–ligand complexes and from 5.072 to 11.09 kcal/mol for the CDPK4–ligand complexes. Among all evaluated compounds, oleanolic acid and ursolic acid exhibited the highest predicted drug-likeness and strong antiprotozoal activity, as supported by PASS predictions. DFT calculations further reinforced their inhibitory potential, with both compounds showing an extremely small energy gap difference of −0.0002 eV. In addition, MD simulations using normal mode analysis (NMA) showed that the candidate inhibitors formed stable complexes with both CDPK3 and CDPK4. © 2026 by the authors.
Biology Department, Faculty of Mathematics and Natural Science, Universitas Negeri Surabaya, Indonesia; Department of Biochemistry, Faculty of Mathematics and Natural Sciences, IPB University, Bogor, Indonesia; Department of Applied Chemistry, Faculty of Engineering, Kyushu University, Japan; Department of Applied Physics, Faculty of Science and Technology, FST, University Kebangsaan Malaysia (UKM), Malaysia; Department of Industrial Biotechnology, Atta Ur Rahman School of Applied Biosciences, National University of Sciences & Technology, Islamabad, Pakistan; Bioinformatics Research Center, Indonesian Institute of Bioinformatics (INBIO Indonesia), Malang, Indonesia; Department of Chemical Engineering, Faculty of Engineering, Universitas Indonesia, Jakarta, Indonesia; Biotechnology Program, Graduate School, IPB University, Bogor, Indonesia
