Studies of Achyranthes aspera Shoot Phytochemicals on Plasmodium falciparum Dihydrofolate Reductase (PfDHFR) Enzymes Targeted in Antimalarial Drug Design
DOI:
https://doi.org/10.54536/jir.v3i3.5476Keywords:
Achyranthes Aspera, Chikutsesusaponin Iva, Gypsogenin-3-O-Glucuronide, Molecular Docking, PfDHFRAbstract
Resistance of Plasmodium falciparum to the first-line antimalarial drug (artemisinin) has been reported in several endemic regions, highlighting the need for new therapeutic alternatives. Medicinal plants are potential sources of bioactive compounds with antimalarial properties. Achyranthes aspera (Amaranthaceae) which is widely distributed in Africa and Nigeria, has shown significant antimalarial activity. This study investigated the in silico inhibitory effects of phytochemicals from the chloroform fraction of A. aspera against the Plasmodium falciparum dihydrofolate reductase (PfDHFR) enzyme. Bioactive compounds were identified and screened using molecular docking via AutoDock Vina 4.2 to evaluate their binding affinities to PfDHFR. Twelve phytochemicals demonstrated promising interactions with the target enzyme. Notably, Chikutsesusaponin iva (-9.4 kcal/mol) and Gypsogenin-3-O-glucuronide (-9.0 kcal/mol) exhibited stronger binding energies than standard inhibitors pyrimethamine (-5.6 kcal/mol) and cycloguanil (-5.8 kcal/mol). These lead compounds formed multiple traditional hydrogen bonds and other interactions within the PfDHFR binding pocket, suggesting a higher spontaneity and stability of binding. Some of the additional active compounds included are Betulin (-7.2 kcal/mol), Causapogenin (-7.8 kcal/mol), Gypsogenic acid (-7.9 kcal/mol), Kaempferol-3-O-galactoside (-6.9 kcal/mol), Lupeol (-7.8 kcal/mol), Lutein (-7.1 kcal/mol), Oleanolic acid (-7.6 kcal/mol), Squalene (-6.6 kcal/mol), and α-Spinasterol (-7.8 kcal/mol). These findings suggest that Chikutsesusaponin iva and Gypsogenin-3-O-glucuronide are promising candidates for antimalarial drug development targeting PfDHFR.
References
Adams, L., Afiadenyo, M., Kwofie, S. K., Wilson, M. D., Kusi, K. A., Obiri-Yeboah, D., Moane, S., & McKeon-Bennett, M. (2023). In silico screening of phytochemicals from Dissotis rotundifolia against Plasmodium falciparum Dihydrofolate Reductase. Phytomedicine Plus, 3(2), 100447. https://doi.org/10.1016/j.phyplu.2023.100447
Adasme, M. F., Linnemann, K. L., Bolz, S. N., Kaiser, F. S., & Haupt, V. J. (2021). Expanding the scope of the protein–ligand interaction profiler to DNA and RNA. Nucleic Acids Research, 49(W1), W530–W534. https://doi.org/10.1093/nar/gkab294
Adeleye, O. A., Femi-Oyewo, M. N., Bamiro, O. A., Bakre, L. G., Alabi, A., Ashidi, J. S., Balogun-Agbaje, O. A., Hassan, O. M., & Fakoya, G. (2021). Ethnomedicinal herbs in African traditional medicine with potential activity for the prevention, treatment, and management of coronavirus disease 2019. Future Journal of Pharmaceutical Sciences, 7(1). https://doi.org/10.1186/s43094-021-00223-5
Akinnusi, P. A., Olubode, S. O., Adebesin, A. O., Osadipe, T. J., Nwankwo, D. O., Adebisi, A. D., Titilayo, I. B., Alo, Y., Owoloye, A. J., & Oyebola, K. M. (2023). Structure-based scoring of anthocyanins and molecular modeling of PfLDH, PfDHODH, and PfDHFR reveal novel potential P. falciparum inhibitors. Informatics in Medicine Unlocked. https://doi.org/10.1016/j.imu.2023.101206
Alagga, A. A., Pellegrini, M. V., & Gupta, V. (2024, February 27). Drug absorption. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK557405/
Aware, C. B., Patil, D. N., Suryawanshi, S. S., Mali, P. R., Rane, M. R., Gurav, R. G., & Jadhav, J. P. (2022). Natural bioactive products as promising therapeutics: A review of natural product-based drug development. South African Journal of Botany, 151, 512–528. https://doi.org/10.1016/j.sajb.2022.05.028
Bas, D. C., Rogers, D. M., & Jensen, J. H. (2008). Very fast prediction and rationalization of pKa values for protein–ligand complexes. Proteins: Structure, Function, and Bioinformatics, 73(3), 765–783. https://doi.org/10.1002/prot.22102
Bayode, T., & Siegmund, A. (2022). Social determinants of malaria prevalence among children under five years: A cross-sectional analysis of Akure, Nigeria. Scientific African, 16, e01196. https://doi.org/10.1016/j.sciaf.2022.e01196
Blessborn, D., Romsing, S., Bergqvist, Y., & Lindegardh, N. (2010). Assay for screening for six antimalarial drugs and one metabolite using dried blood spot sampling, sequential extraction and Ion-Trap detection. Bioanalysis, 2(11), 1839–1847. https://doi.org/10.4155/bio.10.147
Centers for Disease Control and Prevention (CDC). (2024, April 8). Drug resistance in the malaria-endemic world. Malaria. https://www.cdc.gov/malaria/php/public-health-strategy/drug-resistance.html
Chaachouay, N., & Zidane, L. (2024). Plant-derived natural products: A source for drug discovery and development. Drugs and Drug Candidates, 3(1), 184–207. https://doi.org/10.3390/ddc3010011
Choowongkomon, K., Theppabutr, S., Songtawee, N., Day, N. P., White, N. J., Woodrow, C. J., & Imwong, M. (2010). Computational analysis of binding between malarial dihydrofolate reductases and anti-folates. Malaria Journal, 9(1). https://doi.org/10.1186/1475-2875-9-65
Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(1). https://doi.org/10.1038/srep42717
Fernandes, N., Figueiredo, P., Rosário, V. E. D., & Cravo, P. (2007). Analysis of sulphadoxine/pyrimethamine resistance-conferring mutations of Plasmodium falciparum from Mozambique reveals the absence of the dihydrofolate reductase 164L mutant. Malaria Journal, 6(1). https://doi.org/10.1186/1475-2875-6-35
Guan, L., Yang, H., Cai, Y., Sun, L., Di, P., Li, W., Liu, G., & Tang, Y. (2018). ADMET-score – A comprehensive scoring function for evaluation of chemical drug-likeness. MedChemComm, 10(1), 148–157. https://doi.org/10.1039/c8md00472b
Habibi, P., Shi, Y., Grossi-De-Sa, M. F., & Khan, I. (2022). Plants as sources of natural and recombinant antimalaria agents. Molecular Biotechnology, 64(11), 1177–1197. https://doi.org/10.1007/s12033-022-00499-9
Hadni, H., Bakhouch, M., & Elhallaoui, M. (2021). 3D-OSR molecular docking, DFT and ADMET study on quinazoline derivatives to explore novel DHFR inhibition. Journal of Biomolecular Structure and Dynamics, 1–15. https://doi.org/10.1080/0739102.2021.2004233
Heinberg, A., & Kirkman, L. (2015). The molecular basis of antifolate resistance in Plasmodium falciparum: Looking beyond point mutations. Annals of the New York Academy of Sciences, 1342(1), 10–18. https://doi.org/10.1111/nyas.12662
Ikegbunam, M. N., Ejiofor, I. M., Onwuakpa, V., Duru, V. C., Amarachi, A., Oranu, E., Okoyeh, J., & Egieyeh, S. (2022). Virtual screening of selected phytochemicals from four antimalarial plants predicted potential inhibitors of wild type and mutant forms of dihydrofolate reductase-thymidylate synthase in Plasmodium sp. Preprints. https://doi.org/10.20944/preprints202202.0107.v1
Jonnalagadda, S., Suman, P., Morgan, D., & Seay, J. (2017). Recent developments on the synthesis and applications of betulin and betulinic acid derivatives as therapeutic agents. In Studies in Natural Products Chemistry (pp. 45–84). https://doi.org/10.1016/B978-0-444-63930-1.00002-8
Jung, W., Goo, S., Hwang, T., Lee, H., Kim, Y., Chae, J., Yun, H., & Jung, S. (2024). Absorption distribution metabolism excretion and toxicity property prediction utilizing a pre-trained natural language processing model and its applications in early-stage drug development. Pharmaceuticals, 17(3), 382. https://doi.org/10.3390/ph17030382
Lipinski, C. A. (2004). Lead- and drug-like compounds: The rule-of-five revolution. Drug Discovery Today: Technologies, 1(4), 337–341. https://doi.org/10.1016/j.ddtec.2004.11.007
Mankilik, M. M., Longdet, I. Y., & Luka, C. D. (2021). Evaluation of Achyranthes aspera shoot extract as an alternative therapy for malaria. The Journal of Basic and Applied Zoology, 82(1). https://doi.org/10.1186/s41936-021-00211-4
Mankilik, M. M., Paul, J., Mhya, D. H., Luka, C. D., & Longdet, I. Y. (2025). In vivo antiplasmodial studies of Achyranthes aspera fractions and molecular docking studies of its phytochemicals against Plasmodium aspartic proteases targeted in antimalarial drug design. American Journal of Bioscience and Bioinformatics, 4(1), 11–25. https://doi.org/10.54536/ajbb.v4i1.4516
Marrelli, M. T., & Brotto, M. (2016). The effect of malaria and anti-malarial drugs on skeletal and cardiac muscles. Malaria Journal, 15(1). https://doi.org/10.1186/s12936-016-1577-y
Nosten, F., & White, N. J. (2007, December 1). Artemisinin-based combination treatment of falciparum malaria. Defining and Defeating the Intolerable Burden of Malaria III: Progress and Perspectives - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK1713/
Nwankwo, N. J., Paul, J., Gaknung, S. K., Fakdul, T., Simon, M. O., Davou, D. T., Mankilik, M. M., Kutshik, R. J., Yakubu, B., & Longdet, I. Y. (2024, May 31). Genetic insights into Plasmodium falciparum resistance to sulfadoxine-pyrimethamine through a study of the 540-dihydropteroate synthetase gene mutations in Jos, Nigeria. Asian Journal of Biotechnology and Genetic Engineering. https://journalajbge.com/index.php/AJBGE/article/view/131
Paul, J., Nwankwo, N. J., Simon, M. O., Gaknung, S. K., Fakdul, T., Davou, D. T., Mankilik, M. M., Kutshik, R. J., Yakubu, B., & Longdet, I. Y. (2023). Non-synonymous mutations associated with Plasmodium falciparum artemisinin resistant gene (Pfkelch13) in malaria cases, Jos Nigeria. Journal of Advances in Biology & Biotechnology, 26(10), 28–38. https://doi.org/10.9734/jabb/2023/v26i10661
Pereira, V. S. de S., Emery, F. S., Lobo, L., Nogueira, F., Oliveira, J. I. N., Fulco, U. L., Albuquerque, E. L., Katzin, A. M., & de Andrade-Neto, V. F. (2018). In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1,4-naphthoquinone derivatives. Malaria Journal, 17(1). https://doi.org/10.1186/s12936-018-2615-8
Rastelli, G., Pellecchia, M., Sirawaraporn, W., & Parenti, M. D. (2000). Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: Structural basis of antifolate resistance. Bioorganic & Medicinal Chemistry, 8(5), 1117–1128.
Sarkar, R., Nayak, S. L., Suthar, M. K., & Das, M. (2024). Nutraceutical formulations from medicinal plants: A potential therapeutic agent. In Nutraceuticals and Natural Product Derivatives (pp. 391–417). https://doi.org/10.1007/978-981-97-2367-6_19
Shrestha, K. K., Tiwari, N. N., & Ghimire, S. K. (2025). MAPDON–Medicinal and aromatic plant database of Nepal. ResearchGate. https://www.researchgate.net/publication/281288981_MAPDON-Medicinal_and_aromatic_plant_database_of_Nepal
Sun, W., & Shahrajabian, M. H. (2023). Therapeutic potential of phenolic compounds in medicinal plants—Natural health products for human health. Molecules, 28(4), 1845.
Tripathi, H., Bhalera, B., Arya, H., Alotaibi, B. S., Rashidi, S., Higa, M. R., & Bhalt, T. K. (2023). Malaria therapeutics: Are we close enough? Parasites & Vectors, 16(130), 289–294.
Trott, O., & Olson, A. J. (2020). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31, 455–461. https://doi.org/10.1002/jcc.21334
Uzor, P. F., Prasastry, V. D., & Agubats, C. O. (2020). Natural products as sources of antimalarial drugs. Evidence-Based Complementary and Alternative Medicine. https://doi.org/10.1155/2020/9286362
Vestergaard, L. S., & Ringwald, P. (2007, December 1). Responding to the challenge of antimalarial drug resistance by routine monitoring to update national malaria treatment policies. Defining and Defeating the Intolerable Burden of Malaria III: Progress and Perspectives – NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK1708/
White, N. J. (2013). Malaria. In Elsevier eBooks (pp. 532–600.e1). https://doi.org/10.1016/B978-0-7020-5101-2.00044-3
Witcht, K. J., Mok, S., & Fidock, D. A. (2020). Molecular mechanism of drug resistance in Plasmodium falciparum malaria. Annual Review of Microbiology, 74, 431–454. https://doi.org/10.1146/annurev-micro-020518-115546
World Health Organization. (2024). World malaria report 2024. https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2024
World Health Organization. (2025). World Malaria Day 2025. https://www.who.int/campaigns/world-malaria-day/2025
Xiong, G., Wu, Z., Yi, J., Fu, L., Yang, Z., Hsieh, C., Yin, M., Zeng, X., Wu, C., Lu, A., Chen, X., Hou, T., & Cao, D. (2021). ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Research, 49(W1), W5–W14. https://doi.org/10.1093/nar/gkab255
Yang, X., Zhou, J., Wang, T., Zhao, L., Ye, G., Shi, F., Li, Y., Tang, H., Dong, Q., Zhou, X., Xu, M., Rong, Q., Chen, H., Yang, X., & Cai, Y. (2017). A novel method for synthesis of α-spinasterol and its antibacterial activities in combination with ceftiofur. Fitoterapia, 119, 12–19. https://doi.org/10.1016/j.fitote.2017.03.011
Yeung, S., Pongtavornpinyo, W., Hastings, I. M., Mills, A. J., & White, N. J. (2004, August 1). Antimalarial drug resistance, artemisinin-based combination therapy, and the contribution of modeling to elucidating policy choices. The Intolerable Burden of Malaria II: What’s New, What’s Needed - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK3762/
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Mankilik M. Mary, Joel Paul, Peace O. Abaya, Mhya H. Daniel, Kutshik J. Richard, Luka D. Carrol, Longdet Y. Ishaya
This work is licensed under a Creative Commons Attribution 4.0 International License.
