In Silico Investigation of Betalaine Compounds from Hylocereus polyrhizus Peel as Antiplasmodial Agents
DOI:
https://doi.org/10.54832/phj.v8i1.1314Keywords:
In silico, Antiplasmodial, Hylocereus polyrhizusAbstract
Introduction: Malaria is a parasite illness that continues to pose a global health challenge, largely because of the rise of medication resistance. Researchers are concentrating on discovering novel medicines that specifically target critical parasite proteins to address this issue. The peels of Hylocereus polyrhizus (dragon fruit) contain betalains which exhibit antiplasmodial activity. This research examines the efficacy of six betalaines derived from H. polyrhizus peels in inhibiting specific Plasmodium falciparum proteins through in silico techniques.
Methods: The protein structures were acquired from the Protein Data Bank (PDB) and processed by eliminating non-protein molecules. The 3D structures of the betalaine ligands were obtained from PubChem and optimized with Avogadro 1.2.0. Using the Pyrx 0.8 system with Autodock Vina, the ligands were docked to the proteins. The research assessed ADMET characteristics of the ligands utilizing the SwissADME and ProTox-II platforms, respectively.
Results: The molecular docking data indicate that Phyllocactin had the highest binding affinity of -10.7 kcal/mol to PfPNP. Hylocerenin had the highest binding affinity to PfDHFR-TS at -9.4 kcal/mol. The investigation of amino acid interactions indicated that Hylocerenin engages with essential residues, specifically Lys27 and Lys28, in PfDHFR-TS. Regarding ADMET characteristics, all six betalaines exhibited minimal gastrointestinal absorption and lacked permeability across the blood-brain barrier. Moreover, Hylocerenin was anticipated to be non-immunotoxic, presenting a notable benefit over other substances such as Betacyanin and Phyllocactin, which were forecasted to have immunotoxic effects.
Conclusions: Hylocerenin and Phyllocactin are the most promising antiplasmodial possibilities among the examined betalaine compounds. Hylocerenin is a primary candidate for the inhibition of PfDHFR-TS, whereas Phyllocactin is a prominent candidate for the inhibition of PfPNP. The results indicate that betalaine compounds derived from H. polyrhizus peels merit more research as a novel category of antimalarial medicines
Downloads
References
A R Oliveira, G., G D V Morales, B., M O Sousa, R., S Pereira, S., Antunes, D., Caffarena, E. R., & Zanchi, F. B. (2024). Exploring Novel Antimalarial Compounds Targeting Plasmodium falciparum Enoyl-ACP Reductase: Computational and Experimental Insights. ACS Omega, 9(21), 22777–22793. https://doi.org/10.1021/acsomega.3c09893
Akerman, S. E., & Müller, S. (2003). 2-Cys peroxiredoxin PfTrx-Px1 is involved in the antioxidant defence of Plasmodium falciparum. Molecular and Biochemical Parasitology, 130(2), 75–81. https://doi.org/10.1016/S0166-6851(03)00161-0
Alzain, A. A., Ahmed, Z. A. M., Mahadi, M. A., khairy, E. A., & Elbadwi, F. A. (2022). Identification of novel Plasmodium falciparum dihydroorotate dehydrogenase inhibitors for malaria using in silico studies. Scientific African, 16, e01214. https://doi.org/10.1016/j.sciaf.2022.e01214
Banerjee, R., Liu, J., Beatty, W., Pelosof, L., Klemba, M., & Goldberg, D. E. (2002). Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine. Proceedings of the National Academy of Sciences, 99(2), 990–995. https://doi.org/10.1073/pnas.022630099
Dallakyan, S., & Olson, A. J. (2015). Small-molecule library screening by docking with PyRx. Methods in Molecular Biology (Clifton, N.J.), 1263, 243–250. https://doi.org/10.1007/978-1-4939-2269-7_19
Du, X., Li, Y., Xia, Y.-L., Ai, S.-M., Liang, J., Sang, P., Ji, X.-L., & Liu, S.-Q. (2016). Insights into Protein–Ligand Interactions: Mechanisms, Models, and Methods. International Journal of Molecular Sciences, 17(2), 144. https://doi.org/10.3390/ijms17020144
Guggisberg, A. M., Park, J., Edwards, R. L., Kelly, M. L., Hodge, D. M., Tolia, N. H., & Odom, A. R. (2014). A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites. Nature Communications, 5(1), 4467. https://doi.org/10.1038/ncomms5467
Hendra, R., Khodijah, R., Putri, R., Amalia, R., Haryani, Y., Teruna, H. Y., & Abdulah, R. (2021). Cytotoxicity and Antiplasmodial Properties of Different Hylocereus polyrhizus Peel Extracts. Medical Science Monitor Basic Research, 27, e931118-1-e931118-6. https://doi.org/10.12659/MSMBR.931118
Hyde, J. E. (1990). The dihydrofolate reductase-thymidylate synthetase gene in the drug resistance of malaria parasites. Pharmacology & Therapeutics, 48(1), 45–59. https://doi.org/10.1016/0163-7258(90)90017-V
Jain, P., Chakma, B., Patra, S., & Goswami, P. (2014). Potential Biomarkers and Their Applications for Rapid and Reliable Detection of Malaria. BioMed Research International, 2014, 852645. https://doi.org/10.1155/2014/852645
Krishna, S., Pulcini, S., Fatih, F., & Staines, H. (2010). Artemisinins and the biological basis for the PfATP6/SERCA hypothesis. Trends in Parasitology, 26(11), 517–523. https://doi.org/10.1016/j.pt.2010.06.014
Luu, T.-T.-H., Le, T.-L., Huynh, N., & Quintela-Alonso, P. (2021). Dragon fruit: A review of health benefits and nutrients and its sustainable development under climate changes in Vietnam. Czech Journal of Food Sciences, 39(2), 71–94. https://doi.org/10.17221/139/2020-CJFS
Maity, K., Banerjee, T., Prabakaran, N., Surolia, N., Surolia, A., & Suguna, K. (2011). Effect of substrate binding loop mutations on the structure, kinetics, and inhibition of enoyl acyl carrier protein reductase from plasmodium falciparum. IUBMB Life, 63(1), 30–41. https://doi.org/10.1002/iub.412
N., N., C., G. P. D., Chakraborty, C., V., K., D., T. K., V., B., R., S., Lu, A., Ge, Z., & Zhu, H. (2016). Mechanism of artemisinin resistance for malaria PfATP6 L263 mutations and discovering potential antimalarials: An integrated computational approach. Scientific Reports, 6(1), 30106. https://doi.org/10.1038/srep30106
Ojo, K. K., Eastman, R. T., Vidadala, R., Zhang, Z., Rivas, K. L., Choi, R., Lutz, J. D., Reid, M. C., Fox, A. M. W., Hulverson, M. A., Kennedy, M., Isoherranen, N., Kim, L. M., Comess, K. M., Kempf, D. J., Verlinde, C. L. M. J., Su, X., Kappe, S. H. I., Maly, D. J., … Van Voorhis, W. C. (2014a). A Specific Inhibitor of PfCDPK4 Blocks Malaria Transmission: Chemical-genetic Validation. The Journal of Infectious Diseases, 209(2), 275–284. https://doi.org/10.1093/infdis/jit522
Ojo, K. K., Eastman, R. T., Vidadala, R., Zhang, Z., Rivas, K. L., Choi, R., Lutz, J. D., Reid, M. C., Fox, A. M. W., Hulverson, M. A., Kennedy, M., Isoherranen, N., Kim, L. M., Comess, K. M., Kempf, D. J., Verlinde, C. L. M. J., Su, X., Kappe, S. H. I., Maly, D. J., … Van Voorhis, W. C. (2014b). A Specific Inhibitor of PfCDPK4 Blocks Malaria Transmission: Chemical-genetic Validation. The Journal of Infectious Diseases, 209(2), 275–284. https://doi.org/10.1093/infdis/jit522
Orozco, M. I., Moreno, P., Guevara, M., Abonia, R., Quiroga, J., Insuasty, B., Barreto, M., Burbano, M. E., & Crespo-Ortiz, M. D. P. (2023). In silico prediction and in vitro assessment of novel heterocyclics with antimalarial activity. Parasitology Research, 123(1), 75. https://doi.org/10.1007/s00436-023-08089-7
Pallavi, R., Roy, N., Nageshan, R. K., Talukdar, P., Pavithra, S. R., Reddy, R., Venketesh, S., Kumar, R., Gupta, A. K., Singh, R. K., Yadav, S. C., & Tatu, U. (2010). Heat shock protein 90 as a drug target against protozoan infections: Biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug. The Journal of Biological Chemistry, 285(49), 37964–37975. https://doi.org/10.1074/jbc.M110.155317
Park, J., Guggisberg, A., John, A., & Tolia, N. (2015). Cap-domain closure enables diverse substrate recognition by the C2-type haloacid dehalogenase-like sugar phosphatase Plasmodium falciparum HAD1. Acta Crystallographica Section D, 71, 1824–1834. https://doi.org/10.1107/S1399004715012067
Park, J., Guggisberg, A. M., Odom, A. R., & Tolia, N. H. (2015). Cap-domain closure enables diverse substrate recognition by the C2-type haloacid dehalogenase-like sugar phosphatase Plasmodium falciparum HAD1. Acta Crystallographica. Section D, Biological Crystallography, 71(Pt 9), 1824–1834. https://doi.org/10.1107/S1399004715012067
Rajendran, P., Rathinasabapathy, R., Chandra Kishore, S., & Bellucci, S. (2023). Computational-Simulation-Based Behavioral Analysis of Chemical Compounds. Journal of Composites Science, 7(5), 196. https://doi.org/10.3390/jcs7050196
Sama-ae, I., Muengthongon, P., Tohlaeh, A., Rukhachan, W., Kiattikul, P., Samaeng, F., Mitklin, A., Rahman, Md. A., Tedasen, A., Kwankaew, P., Kotepui, M., & Kepan, A. (2025). Penicillium-Derived Inhibitors of Plasmodium falciparum Lactate Dehydrogenase (PfLDH): A Computational Approach for Novel Antimalarial Therapy Development. Scientifica, 2025, 8838031. https://doi.org/10.1155/sci5/8838031
Seetin, S., Saparpakorn, P., Vanichtanankul, J., Vitsupakorn, D., Yuthavong, Y., Kamchonwongpaisan, S., & Hannongbua, S. (2023). Key interactions of pyrimethamine derivatives specific to wild-type and mutant P. falciparum dihydrofolate reductase based on 3D-QSAR, MD simulations and quantum chemical calculations. Journal of Biomolecular Structure & Dynamics, 41(12), 5728–5743. https://doi.org/10.1080/07391102.2022.2096114
Setlur, A. (2023). In-silico-based toxicity investigation of natural repellent molecules against the human proteome: A safety profile design v1. https://doi.org/10.17504/protocols.io.4r3l225nql1y/v1
Shi, W., Ting, L.-M., Kicska, G. A., Lewandowicz, A., Tyler, P. C., Evans, G. B., Furneaux, R. H., Kim, K., Almo, S. C., & Schramm, V. L. (2004a). Plasmodium falciparum Purine Nucleoside Phosphorylase. Journal of Biological Chemistry, 279(18), 18103–18106. https://doi.org/10.1074/jbc.C400068200
Shi, W., Ting, L.-M., Kicska, G. A., Lewandowicz, A., Tyler, P. C., Evans, G. B., Furneaux, R. H., Kim, K., Almo, S. C., & Schramm, V. L. (2004b). Plasmodium falciparum purine nucleoside phosphorylase: Crystal structures, immucillin inhibitors, and dual catalytic function. The Journal of Biological Chemistry, 279(18), 18103–18106. https://doi.org/10.1074/jbc.C400068200
Sibley, C. (2014). Understanding drug resistance in malaria parasites: Basic science for public health. Molecular and Biochemical Parasitology, 195. https://doi.org/10.1016/j.molbiopara.2014.06.001
Sprenger, J., Svensson, B., Hålander, J., Carey, J., Persson, L., & Al-Karadaghi, S. (2015). Three-dimensional structures of Plasmodium falciparum spermidine synthase with bound inhibitors suggest new strategies for drug design. Acta Crystallographica Section D: Biological Crystallography, 71(3), 484–493. https://doi.org/10.1107/S1399004714027011
Syed, S. F., Bhattacharya, A., & Choudhary, S. (2025). Molecular insights into the aspartate protease Plasmepsin II activity inhibition by fluoroquinolones: A pathway to antimalarial drug development. International Journal of Biological Macromolecules, 285, 138369. https://doi.org/10.1016/j.ijbiomac.2024.138369
Wybraniec, S., Platzner, I., Geresh, S., Gottlieb, H. E., Haimberg, M., Mogilnitzki, M., & Mizrahi, Y. (2001). Betacyanins from vine cactus Hylocereus polyrhizus. Phytochemistry, 58(8), 1209–1212. https://doi.org/10.1016/S0031-9422(01)00336-3
Yu, Z.-R., Weng, Y.-M., Lee, H.-Y., & Wang, B.-J. (2023). Partition of bioactive components from red pitaya fruit (Hylocereus polyrhizus) peels into different fractions using supercritical fluid fractionation technology. Food Bioscience, 51, 102270. https://doi.org/10.1016/j.fbio.2022.102270
