The Potential of Murraya koenigii as a PfAp4AH Inhibitor for Malaria Drug Development
Abstract
Murraya koenigii, a medicinal plant from the Rutaceae family, is traditionally used as a flavoring agent and is known for its bioactive carbazole alkaloids. Native to the Indo-Malaysian region, China, Sri Lanka, and New Caledonia, this plant has shown potential for therapeutic applications, including antimalarial activity. Malaria, particularly caused by Plasmodium falciparum, remains a significant global health challenge due to rising drug resistance. PfAp4AH, an enzyme involved in diadenosine tetraphosphate (Ap4A) metabolism, has emerged as a promising target for novel antimalarial drugs.
This study employed computational approaches—binding site prediction and virtual screening through molecular docking—to identify potential PfAp4AH inhibitors from 156 carbazole alkaloids derived from M. koenigii. Ten compounds demonstrated stronger binding affinities than ATP, with compound 1 showing the highest inhibitory potential through strong and diverse interactions with key residues Tyr87, His43, Pro133, and Leu136. These findings underscore the importance of specific ligand–residue interactions in determining binding strength. The identified compounds, especially compound 1, present promising leads for further experimental validation. While initial bioactivity and toxicity profiles are favorable, comprehensive bioavailability and toxicological evaluations are needed to advance these compounds as antimalarial drug candidates.
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References
Ali, F., Wali, H., Jan, S., Zia, A., Aslam, M., Ahmad, I., Afridi, S. G., Shams, S., & Khan, A. (2021). Analysing the essential proteins set of Plasmodium falciparum PF3D7 for novel drug targets identification against malaria. Malaria Journal, 20(1), 335. https://doi.org/10.1186/s12936-021-03865-1
Ashkenazy, H., Abadi, S., Martz, E., Chay, O., Mayrose, I., Pupko, T., & Ben-Tal, N. (2016). ConSurf 2016: An improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Research, 44(W1), W344–W350. https://doi.org/10.1093/nar/gkw408
Ashley, E. A., Phyo, A. P., & Woodrow, C. J. (2018). Malaria. The Lancet, 391(10130), 1608–1621. https://doi.org/10.1016/S0140-6736(18)30324-6
Franyoto, Y. D., Nurrochmad, A., & Fakhrudin, N. (2024). Murraya koenigii L. Spreng.: An updated review of chemical composition, pharmacological effects, and toxicity studies. Journal of Applied Pharmaceutical Science. https://doi.org/10.7324/JAPS.2024.169254
Ishikura, M., Imaizumi, K., & Katagiri, N. (2000). A concise preparation of yuehchukene and its analogues (Vol. 53).
Ito, C., Itoigawa, M., Nakao, K., Murata, T., Tsuboi, M., Kaneda, N., & Furukawa, H. (2006). Induction of apoptosis by carbazole alkaloids isolated from Murraya koenigii. Phytomedicine, 13(5), 359–365. https://doi.org/10.1016/j.phymed.2005.03.010
Jeyakanthan, J., Kanaujia, S. P., Nishida, Y., Nakagawa, N., Praveen, S., Shinkai, A., Kuramitsu, S., Yokoyama, S., & Sekar, K. (2010). Free and ATP-bound structures of Ap4A hydrolase from Aquifex aeolicus V5. Acta Crystallographica Section D: Biological Crystallography, 66(2), 116–124. https://doi.org/10.1107/S0907444909047064
Kong, Y.-C., Cheng, K.-F., Cambie, R. C., & Waterman, P. G. (1985). Yuehchukene: A novel indole alkaloid with anti-implantation activity. Journal of the Chemical Society, Chemical Communications, (2), 47. https://doi.org/10.1039/c39850000047
Patel, O. P. S., Mishra, A., Maurya, R., Saini, D., Pandey, J., Taneja, I., Raju, K. S. R., Kanojiya, S., Shukla, S. K., Srivastava, M. N., Wahajuddin, Tamrakar, A. K., Srivastava, A. K., & Yadav, P. P. (2016a). Naturally occurring carbazole alkaloids from Murraya koenigii as potential antidiabetic agents. Journal of Natural Products, 79(5), 1276–1284. https://doi.org/10.1021/acs.jnatprod.5b00883
Patel, O. P. S., Mishra, A., Maurya, R., Saini, D., Pandey, J., Taneja, I., Raju, K. S. R., Kanojiya, S., Shukla, S. K., Srivastava, M. N., Wahajuddin, Tamrakar, A. K., Srivastava, A. K., & Yadav, P. P. (2016b). Naturally occurring carbazole alkaloids from Murraya koenigii as potential antidiabetic agents. Journal of Natural Products, 79(5), 1276–1284. https://doi.org/10.1021/acs.jnatprod.5b00883
Saglam, M. F. (2022). Synthesis, characterization and thermal analysis of novel methylene bridged bis-carbazole based bisbenzimidazoles. Hittite Journal of Science and Engineering, 9(4), 281–286. https://doi.org/10.17350/HJSE19030000281
Setyawati, I., Setiawan, A. G., Nemchinova, M., & Vidilaseris, K. (2024). The potential inhibitory mechanism of EGCG against the chikungunya virus targeting non-structural protein 2 through molecular dynamics simulation. Scientific Reports, 14(1), 29797. https://doi.org/10.1038/s41598-024-81287-0
Sharma, A., Yogavel, M., & Sharma, A. (2016a). Structural and functional attributes of malaria parasite diadenosine tetraphosphate hydrolase. Scientific Reports, 6(1), 19981. https://doi.org/10.1038/srep19981
Sharma, A., Yogavel, M., & Sharma, A. (2016b). Structural and functional attributes of malaria parasite diadenosine tetraphosphate hydrolase. Scientific Reports, 6(1), 19981. https://doi.org/10.1038/srep19981
Uvarani, C., Sankaran, M., Jaivel, N., Chandraprakash, K., Ata, A., & Mohan, P. S. (2013). Bioactive dimeric carbazole alkaloids from Murraya koenigii. Journal of Natural Products, 76(6), 993–1000. https://doi.org/10.1021/np300464t
White, N. J., Pukrittayakamee, S., Hien, T. T., Faiz, M. A., Mokuolu, O. A., & Dondorp, A. M. (2014). Malaria. The Lancet, 383(9918), 723–735. https://doi.org/10.1016/S0140-6736(13)60024-0
World Health Organization (WHO). (2022). World malaria report 2022.
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