Antimalarial flavonoid glycoside from Carica papaya with inhibitory potential against Plasmodium falciparum dihydrofolate reductase thymidylate synthase: an in-silico study

Main Article Content

Dewa Ayu Agus Sri Laksemi
I Dewa Ayu Inten Dwi Primayanti
I Wayan Surudarma
Putu Ayu Asri Damayanti
Ni Made Pitri Susanti

Abstract

BACKGROUND
Carica papaya is traditionally used to treat malaria. The mechanism of action of the active constituents may be determined by molecular docking. This study therefore examined the in silico antimalarial activity of selected compounds from Carica papaya using Plasmodium falciparum dihydrofolate reductase thymidylate synthase (PfDHFR-TS) as target protein.


METHODS
Antimalarial activity screening of Carica papaya compounds was done in silico using AutoDock 4.2 software which was equipped with Autodock tools 1.5.6 for preparation. Five compounds contained in Carica papaya leaves, i.e. quercitrin, isoquercitrin, carpaine, caricaxanthin, and violaxanthin were successfully docked with the target protein. The molecular docking method is declared valid if the RMSD obtained is not more than 2 Å. In vitro evaluation of the test compounds as antimalarials was accomplished by determining their inhibitory activity against dihydrofolate reductase thymidylate synthase (PfDHFR-TS) which plays a role in the synthesis of nucleotides needed by Plasmodium falciparum.


RESULTS
Validation of Plasmodium falciparum DHFR-TS with PDB ID 1J3I showed an RMSD value of 1.58 Å. The docking results showed that quercitrin, isoquercitrin, carpaine, and caricaxanthin showed negative energy values similar to the native ligand. Therefore the four compounds have good affinity for the target protein, while violaxanthin shows a positive energy value, indicating no affinity for the target protein.


CONCLUSION
Based on binding affinity values and molecular interactions, isoquercitrin and quercitrin have inhibitory activity against dihydrofolate reductase thymidylate synthase (PfDHFR-TS), such that they have potential as natural antimalarial candidates.

Article Details

Section

Original Articles

How to Cite

Antimalarial flavonoid glycoside from Carica papaya with inhibitory potential against Plasmodium falciparum dihydrofolate reductase thymidylate synthase: an in-silico study. (2025). Universa Medicina, 44(1), 26-33. https://doi.org/10.18051/UnivMed.2025.v44.26-33

References

U.S. Center for Disease Control and Prevention. Malaria's impact worldwide. Atlanta : U.S. Center for Disease Control and Prevention;2023.

Rosenthal PJ, Asua V, Bailey JA, et al. The emergence of artemisinin partial resistance in Africa: how do we respond? Lancet Infect Dis 2024;24:e591-e600. doi: 10.1016/S1473-

(24)00141-5.

Paaijmans KP, Lobo NF. Gaps in protection: the actual challenge in malaria elimination. Malar J 2023;22:46. doi: 10.1186/s12936-023-04473-x.

Dhiman S. Are malaria elimination efforts on right track? An analysis of gains achieved and challenges ahead. Infect Dis Poverty 2019; 14:1-

doi:10.1186/s40249-019-0524-x.

Zhu L, van der Pluijm RW, Kucharski M, et al. Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response. Commun Biol 2022;5:1-

doi:10.1038/s42003-022-03215-0.

Tang YQ, Ye Q, Huang H, Zheng WY. An overview of available antimalarials: discovery, mode of action and drug resistance. Curr Mol Med 2020;20:583-92. doi:

2174/1566524020666200207123253.

Belete TM. Recent progress in the development of new antimalarial drugs with novel targets. Drug Des Devel Ther 2020;14:3875-89. doi: 10.2147/DDDT.S265602.

Agu PC, Afiukwa CA, Orji OU, et al. Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management. Sci Rep 2023;13398:1-18. doi:10.1038/s41598- 023-40160-2.

Paggi JM, Pandit A, Dror RO. The art and science of molecular docking. Annu Rev Biochem 2024;93:389–410. doi:10.1146/annurev- biochem-030222-120000.

Shamshad H, Bakri R, Mirza AZ. Dihydrofolate reductase, thymidylate synthase, and serine hydroxy methyltransferase: successful targets against some infectious diseases. Mol Biol Rep 2022;49:6659-91. doi: 10.1007/s11033-022-

-8.

Orfali Gd, Duarte AC, Bonadio V, et al. Review of anticancer mechanisms of isoquercitin. World J Clin Oncol 2016;7:189-99. doi: 10.5306/wjco.v7.i2.189.

Hamed ANE, Abouelela ME, El Zowalaty AE, Badr MM, Abdelkader MSA. Chemical constituents from Carica papaya Linn. leaves as potential cytotoxic, EGFRwt and aromatase (CYP19A) inhibitors; a study supported by molecular docking. RSC Adv 2022;12:9154-62. doi: 10.1039/d1ra07000b.

Keval R, Ganatra T. Basics, types and applications of molecular docking: a review. IP Int J Compr Adv Pharmacol 2022;7:12-6. Doi: 10.18231/j.ijcaap.2022.003.

Stanzione F, Giangreco I, Cole JC. Use of molecular docking computational tools in drug discovery. Prog Med Chem 2021;60:273-343. doi: 10.1016/bs.pmch.2021.01.004.

Memvanga PB, Tona GL, Mesia GK, Lusakibanza MM, Cimanga RK. Antimalarial activity of medicinal plants from the Democratic Republic of Congo: a review. J Ethnopharmacol 2015;169:76-98,

https://doi.org/10.1016/j.jep.2015.03.075.

Ntie-Kang F, Amoa OP, Lifongo LL, Ndom JC, Sippl W, Mbaze LM. The potential of antimalarial compounds derived from African medicinal plants, part II: a pharmacological evaluation of non-alkaloids and non-terpenoids. Malar J

;13:81. https://doi.org/10.1186/1475-2875-

-81.].

Barmade MA, Murumkar PR, Sharma MK, Shingala KP, Giridhar RR, Yadav MR. Discovery of antimalarial agents through application of in silico studies. Comb Chem High Throughput Screen 2015;18:151-87.

https://doi.org/10.2174/13862073186661412291 25852.

Sahayarayan J, Soundar Rajan K, Nachiappan M, et al. Identification of potential drug target in malarial disease using molecular docking analysis. Saudi J Biol Sci 2020;27:3327-33, https://doi.org/10.1016/j.sjbs.2020.10.019.

Fang J, Liu C, Wang Q, Lin P, Cheng F. In silico polypharmacology of natural products. Brief Bioinform 2018;19:1153-71, https://doi.org/10.1093/bib/bbx045.

Tang SM, Deng XT, Zhou J, Li QP, Ge XX, Miao

L. Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects. Biomed Pharmacother 2020;121: 1-7. doi: 10.1016/j.biopha.2019.109604.

Salehi B, Machin L, Monzote L, et al. Therapeutic potential of quercetin: new insights and perspectives for human health. ACS Omega 2020;5:11849-72. doi:

1021/acsomega.0c01818.

Carrillo-Martinez EJ, Flores-Hernández FY, Salazar-Montes AM, Nario-Chaidez HF, Hernández-Ortega LD. Quercetin, a flavonoid with great pharmacological capacity. Molecules 2024;29:1000.

https://doi.org/10.3390/molecules29051000.

Wróbel A, Arciszewska K, Maliszewski D, Drozdowska D. Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors. J Antibiot (Tokyo) 2020;73:5-27. doi: 10.1038/s41429-019-0240-6.

Zothantluanga JH, Aswin SK, Rudrapal M, Cheita

D. Antimalarial flavonoid-glycoside from Acacia pennata with inhibitory potential against PfDHFR-TS: an in-silico study. Biointerface Res Appl Chem 2022;12:4871–87.

https://doi.org/10.33263/BRIAC124.48714887.

Magozwi DK, Dinala M, Mokwana N, et al. Flavonoids from the genus Euphorbia: isolation, structure, pharmacological activities and structure-activity relationships. Pharmaceuticals (Basel) 2021;14:428. doi: 10.3390/ph14050428.

Senthilvel P, Lavanya P, Kumar KM, et al. Flavonoid from Carica papaya inhibits NS2B- NS3 protease and prevents dengue 2 viral assembly. Bioinformation 2013;9:889-95. doi: 10.6026/97320630009889.

Rampadarath A, Balogun FO, Pillay C, Sabiu S. Identification of flavonoid C-glycosides as promising antidiabetics targeting protein tyrosine

phosphatase 1B. J Diabetes Res 2022;2022:6233217. doi: 10.1155/2022/6233217.

Chaniad P, Mungthin M, Payaka A, Viriyavejakul P, Punsawad C. Antimalarial properties and molecular docking analysis of compounds from Dioscorea bulbifera L. as new antimalarial agent candidates. BMC Complement Med Ther 2021

;21:144. doi: 10.1186/s12906-021-03317-y.

Rani SS, Vedavijaya T, Sree P K, et al. A comprehensive analysis of phytochemical composition, acute toxicity assessment, and antioxidant potential of ethanolic extract of Carica papaya seeds. Cureus 2023;15:e49686. doi: 10.7759/cureus.49686.

Singh IV, Mishra S. Molecular docking analysis of pyrimethamine derivatives with Plasmodium falciparum dihydrofolate reductase. Bioinformation 2018;14:232-5. doi: 10.6026/97320630014232.

Dasgupta T, Anderson KS. Probing the role of parasite-specific, distant structural regions on communication and catalysis in the bifunctional thymidylate synthase-dihydrofolate reductase from Plasmodium falciparum. Biochemistry 2008;47:1336-45. doi: 10.1021/bi701624u.

Akinwumi IA, Faleti AI, Owojuyigbe AP, Raji FM, Alaka OM. In silico studies of bioactive compounds selected from four African plants with inhibitory activity against Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (pfDHFR-TS). J Adv Pharm Res

;6:107-22. DOI:

21608/aprh.2022.139794.1175.

Gogoi N, Chetia D, Gogoi B, Das A. Multiple- targets directed screening of flavonoid compounds from Citrus species to find out antimalarial lead with predicted mode of action: an in silico and whole cell based in vitro approach. Curr Comput-aided Drug Des 2021;17:69-82. https://doi.org/10.2174/15734099166661912261 03000.

Adams L, Afiadenyo M, Kwofie SK, et al. In silico screening of phytochemicals from Dissotis rotundifolia against Plasmodium falciparum dihydrofolate reductase. Phytomedicine Plus 2023;3:100447.

https://doi.org/10.1016/j.phyplu.2023.100447.

Hasan MM, Khan Z, Chowdhury MS, Khan MA, Moni MA, Rahman MH. In silico molecular docking and ADME/T analysis of quercetin compound with its evaluation of broad-spectrum therapeutic potential against particular diseases. Inform Med Unlocked 2022;29:100894. doi:10.1016/j.imu.2022.100894.

Mbikay M, Chrétien M. Isoquercetin as an anti- covid-19 medication: a potential to realize. Front Pharmacol 2022;13:830205. doi: 10.3389/fphar.2022.830205.

Sudi S, Chin YZ, Wasli NS, et al. Carpaine promotes proliferation and repair of H9c2 cardiomyocytes after oxidative insults. Pharmaceuticals (Basel) 2022;15:230. doi: 10.3390/ph15020230.