Resistance to conventional antifolates such as pyrimethamine is increasingly widespread in Plasmodium falciparum due to mutations in the dihydrofolate reductase thymidylate synthase (pfDHFR-TS) enzyme, particularly the double mutation C59R+S108N. This study explores the potential of novel 1,6-dihydro-1,3,5-triazine-2,4-diamine-based inhibitors against mutant pfDHFR-TS using a molecular docking approach. The target structure (PDB ID: 1J3J) and ligands were optimized using the semi-empirical PM6 method with partial charges calculated via AM1-BCC, followed by docking using Dock6. The results indicate that 10-(benzyloxy)-6,8,10-triazaspiro [4.5]deca-6,8-diene-7,9-diamine exhibits stronger binding affinity than CP6, a known antimalarial compound. These findings highlight the potential of triazine derivatives as novel inhibitors targeting antifolate-resistant pfDHFR TS mutants.
Kyei L, K., Gasu, E. N., Ampomah, G. B., Mensah, J. O., & Borquaye, L. S. (2022). An In Silico Study of the Interactions of Alkaloids from Cryptolepis sanguinolenta with Plasmodium falciparum Dihydrofolate Reductase and Dihydroorotate Dehydrogenase. Journal of Chemistry, 2022. https://doi.org/10.1155/2022/5314179
Siswanto, I., Pranowo, H. D., & Mudasir. (2019). Docking of New Designed Compound Derived from 1,6-dihydro-1,3,5-triazine-2,4-diamine Toward Quadruple Mutant Plasmodium Dihydrofolate Reductase. Indonesian Journal of Chemistry, 19(3), 777-785. https://doi.org/10.22146/ijc.39943
World Health Organization. (2025). World malaria report 2025: addressing the threat of antimalarial drug resistance. World Health Organization.
Yuvaniyama, J., Chitnumsub, P., Kamchonwongpaisan, S., Vanichtanankul, J., Sirawaraporn, W., Taylor, P., & Walkinshaw, M. D. (2003). Insights into Antifolate Resistance from Malarial DHFR–TS Structures. Nature Structural Biology, 10(5), 357–365. https://doi.org/10.1038/nsb921