Author(s): Faisal Akhmal Muslikh, Dian Nurmawati, Syahputra Wibowo, Agnis Pondineka Ria Aditama, Raymond Rubianto Tjandrawinata, Maximus Markus Taek

Email(s): maximusmt2012@unwira.ac.id

DOI: 10.52711/0974-360X.2026.00475   

Address: Faisal Akhmal Muslikh1, Dian Nurmawati2, Syahputra Wibowo3, Agnis Pondineka Ria Aditama4, Raymond Rubianto Tjandrawinata5, Maximus Markus Taek6*
1Department of Pharmacy, Faculty of Pharmacy, Hang Tuah University, Surabaya 60111, Indonesia.
2Department of Pharmacy, Faculty of Health Science, Kadiri University, Kediri 64115, Indonesia.
3Eijkman Research Center for Molecular Biology, National Research and Innovation Agency, Bogor 16911, Indonesia.
4Department of Pharmacy, Health Polytechnic of Jember, Jember 68125, Indonesia.
5Center for Pharmaceutical and Nutraceutical Research and Policy, Atma Jaya Catholic University of Indonesia, Jakarta 12930, Indonesia.
6Department of Chemistry, Faculty of Sciences and Technology, Widya Mandira Catholic University, Kupang 85361, Indonesia.
*Corresponding Author

Published In:   Volume - 19,      Issue - 7,     Year - 2026


ABSTRACT:
Malaria remains a global health concern due to drug resistance in Plasmodium falciparum, prompting the search for novel therapies. Fatoua pilosa, a traditional medicinal plant from Timor Island Indonesia, has shown potential antimalarial activity. This research explores the antimalarial potential of F. pilosa by applying an integrative in silico approach that incorporates network pharmacology and molecular docking analyses. Nineteen bioactive compounds identified from F. pilosa were analyzed for pharmacological targets using SEA and SwissTargetPrediction, while malaria-related genes were sourced from OMIM, GeneCards, and DisGeNET. Protein–protein interaction (PPI) networks, pathway enrichment, and docking simulations with Falcipain-3 (FP3) were conducted to identify key molecular interactions. A total of 468 overlapping targets were identified between F. pilosa compounds and malaria-related genes. Network analysis highlighted STAT3 as a central node, with enrichment in immune-related pathways (e.g., MAPK cascade). ADME and toxicity analysis via SwissADME and ProTox-III revealed favorable drug-like properties in most compounds. Molecular docking indicated that cycloartenol (M9) exhibited strong binding affinity to FP3 (Vina score: –10.1 kcal/mol), comparable to the native ligand. The identified targets and pathways suggest that F. pilosa compounds may exert antimalarial effects through immune modulation and inhibition of hemoglobin-degrading enzymes. Cycloartenol (M9), in particular, shows promise as an FP3 inhibitor with acceptable pharmacokinetic and safety profiles. This study supports the antimalarial potential of F. pilosa, especially cycloartenol, as a promising candidate for further experimental validation and drug development against P. falciparum.


Cite this article:
Faisal Akhmal Muslikh, Dian Nurmawati, Syahputra Wibowo, Agnis Pondineka Ria Aditama, Raymond Rubianto Tjandrawinata, Maximus Markus Taek. Integrative Network Pharmacology and Molecular Docking of Phytochemicals of Fatuoa pilosa in Targeting Falcipain-3 for Malaria Therapy. Research Journal of Pharmacy and Technology. 2026;19(7):3341-0. doi: 10.52711/0974-360X.2026.00475

Cite(Electronic):
Faisal Akhmal Muslikh, Dian Nurmawati, Syahputra Wibowo, Agnis Pondineka Ria Aditama, Raymond Rubianto Tjandrawinata, Maximus Markus Taek. Integrative Network Pharmacology and Molecular Docking of Phytochemicals of Fatuoa pilosa in Targeting Falcipain-3 for Malaria Therapy. Research Journal of Pharmacy and Technology. 2026;19(7):3341-0. doi: 10.52711/0974-360X.2026.00475   Available on: https://www.rjptonline.org/AbstractView.aspx?PID=2026-19-7-62


REFERENCES: 
1.    Wardani AK, Safwan S, Hapsari NP, Hendriyani I, Ridwansyah MT, Wahid AR. Antimalarial activity of ethyl acetate and n-hexane fractions of ashitaba leaves (Angelica keiskei K.). Research Journal of Pharmacy and Technology. 2023; 16(3): 1314-1318. https://doi.org/10.52711/0974-360X.2023.00216.
2.    Boualam MA, Pradines B, Drancourt M, Barbieri R. Malaria in Europe: a historical perspective. Frontiers in Medicine. 2021; 8: 691095. https://doi.org/10.3389/fmed.2021.691095
3.    Sumbe RR, and Barkade GD. A systematic review on malaria. Indian Journal of Pharmacy and Pharmacology. 2023; 10(2): 54-63. https://doi.org/10.18231/j.ijpp.2023.014
4.    Savi MK. An overview of malaria transmission mechanisms, control, and modeling. Medical Sciences. 2022; 11(1): 3. https://doi.org/10.3390/medsci11010003  
5.    Antony HA, and Parija SC. Antimalarial drug resistance: an overview. Tropical parasitology. 2016; 6(1): 30-41. https://doi.org/10.4103/2229-5070.175081
6.    Thillainayagam M, and Ramaiah S. Mosquito, malaria and medicines-A Review. Research Journal of Pharmacy and Technology. 2016; 9(8): 1268-1276. https://doi.org/10.5958/0974-360X.2016.00241.9
7.    Malaria. 2024. Available from: https://www.who.int/news-room/fact-sheets/detail/malaria. [Last accessed on 21 may 2025]
8.    Uwimana A, Legrand E, Stokes BH, Ndikumana JLM, Warsame M, Umulisa N, ... and Menard D. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nature medicine. 2020; 26(10): 1602-1608. https://doi.org/10.1038/s41591-020-1005-2
9.    Niba PTN, Nji AM, Chedjou JPK, Hansson H, Hocke EF, Ali IM, ... and Mbacham WF. Evolution of Plasmodium falciparum antimalarial drug resistance markers post-adoption of artemisinin-based combination therapies in Yaounde, Cameroon. International Journal of Infectious Diseases. 2023; 132: 108-117. https://doi.org/10.1016/j.ijid.2023.03.050
10.    Bekono BD, Ntie-Kang F, Owono Owono LC, Megnassan E. Targeting cysteine proteases from Plasmodium falciparum: A general overview, rational drug design and computational approaches for drug discovery. Current Drug Targets. 2018; 19(5): 501-526. https://doi.org/10.2174/1389450117666161221122432
11.    Bekono BD, Esmel AE, Dali B, Ntie-Kang F, Keita M, Owono LC, Megnassan E. Computer-aided design of peptidomimetic inhibitors of falcipain-3: QSAR and pharmacophore models. Scientia Pharmaceutica. 2021; 89(4): 44. https://doi.org/10.3390/scipharm89040044
12.    Maslachah L, and Purwitasari N. Antimalarial activity of nano phytomedicine fraction of Syzygium cumini fruit in rodent malaria. Research Journal of Pharmacy and Technology. 2023; 16(9): 4288-4294. https://doi.org/10.52711/0974-360X.2023.00702
13.    Rojas P, Jung-Cook H, Ruiz-Sánchez E, Rojas-Tomé IS, Rojas C, López-Ramírez AM, Reséndiz-Albor AA. Historical aspects of herbal use and comparison of current regulations of herbal products between Mexico, Canada and the United States of America. International Journal of Environmental Research and Public Health. 2022; 19(23): 15690. https://doi.org/10.3390/ijerph192315690
14.    Tahir M, Upadhyay DK, Iqbal MZ, Rajan S, Iqbal MS, Albassam AA. Knowledge of the use of herbal medicines among community pharmacists and reporting their adverse drug reactions. Journal of Pharmacy and Bioallied Sciences. 2020; 12(4): 436-443. https://doi.org/10.4103/jpbs.jpbs_263_20
15.    Sasidharan S, Chen Y, Saravanan D, Sundram KM, Latha LY. Extraction, isolation and characterization of bioactive compounds from plants’ extracts. African journal of traditional, complementary and alternative medicines. 2011; 8(1).
16.    Singh DB, Pathak RK, Rai D. From traditional herbal medicine to rational drug discovery: strategies, challenges, and future perspectives. Revista Brasileira de Farmacognosia. 2022; 32(2): 147-159. https://doi.org/10.1007/s43450-022-00235-z
17.    Agarwal AK, Yadav CP, Kuity P, Mishra J. Development of antimalarial pharmacotherapy and its importance in malaria treatment/public health program. Asian Journal of Pharmaceutical Analysis. 2022; 12(4): 233-242. https://doi.org/10.52711/2231-5675.2022.00038
18.    Taek MM, Prajogo EW, Agil M. The prevention and treatment of malaria in traditional medicine of Tetun ethnic people in West Timor Indonesia. Open Access Journal of Complementary and Alternative Medicine. 2019; 1: 76-84. http://dx.doi.org/10.32474/OAJCAM.2019.01.000121
19.    Taek MM, Tukan GD, Prajogo BEW, Agil M. Antiplasmodial activity and phytochemical constituents of selected antimalarial plants used by native people in west timor Indonesia. Turkish Journal of Pharmaceutical Sciences. 2021; 18(1): 80. https://doi.org/10.4274/tjps.galenos.2019.29000
20.    Indradi RB, Muhaimin M, Barliana MI, Khatib A. (2023). Potential Plant-based new antiplasmodial agent used in Papua Island, Indonesia. Plants. 2023; 12(9): 1813. https://doi.org/10.3390/plants12091813
21.    Ifandi S, and Sulistiyaningsih Y. Ethnopharmacognosy of Medicinal Plants of the Kaili Tribein Tompu, Central Sulawesi. Pharmaqueous: Jurnal Ilmiah Kefarmasian. 2022; 4(2): 45-52.
22.    Tukan MMNM, Falah S, Andrianto D, Najmah N. Antioxidant Activity and Inhibition of Α-Glucosidase from Yellow Root Extract (Fatuoa Pilosa Gaudich) In Vitro. Jambura Journal of Chemistry. 2023; 5(2): 104-115. https://doi.org/10.34312/jambchem.v5i2.20503
23.    Anywar G, and Muhumuza E. Bioactivity and toxicity of coumarins from African medicinal plants. Frontiers in Pharmacology. 2024; 14: 1231006. https://doi.org/10.3389/fphar.2023.1231006
24.    Tjandrawinata RR, Amalia AW, Tuna H, Said VN, Tan S. Molecular mechanisms of network pharmacology-based immunomodulation of huangqi (Astragali Radix). Jurnal Ilmu Kefarmasian Indonesia. 2022; 20(2): 184-195. https://doi.org/10.35814/jifi.v20i2.1301
25.    Taek MM, Muslikh FA, Maulana S, Paneo DR, Aszari EH, Azzahra A, ... and Ma'arif B. Network Pharmacology Analysis of Secondary Metabolites from Alstonia spectabilis for Antimalaria Activity Prediction. Egyptian Journal of Chemistry. 2025; 68(5): 53-60. https://doi.org/10.21608/ejchem.2024.301691.9952
26.    Puspitasari PA, Pratitis VE, Wibowo S, Wijayanti N, Sofyantoro F. In Silico Study of Neoagaro-Oligosaccharides (NAOS) Anti-Inflammatory Activity: Molecular Docking with iNOS and COX-2 Proteins. Pertanika J. Trop. Agric. Sci. 2025; 48(1): 279-293. https://doi.org/10.47836/pjtas.48.1.15
27.    Muslikh FA, Samudra RR, Ma’arif B, Ulhaq ZS, Hardjono S, Agil M. In silico molecular docking and ADMET analysis for drug development of phytoestrogens compound with its evaluation of neurodegenerative diseases. Borneo Journal of Pharmacy. 2022; 5(4): 357-366. https://doi.org/10.33084/bjop.v5i4.3801
28.    De Borja JR, and Cabrera HS. In Silico Drug Screening for Hepatitis C Virus Using QSAR-ML and Molecular Docking with Rho-Associated Protein Kinase 1 (ROCK1) Inhibitors. Computation. 2024; 12(9): 175. https://doi.org/10.3390/computation12090175
29.    Kanji S, and Mondal S. In Silico exploration for potent phytochemicals targeting Helicobacter pylori: assessment of ADMET profiles and molecular docking analysis. Discover Chemistry. 2024; 1(21). https://doi.org/10.1007/s44371-024-00028-4
30.    Jiang C, Liu Y, Xu H. Network-Pharmacology-Based Mechanism Elucidation and Validation for Phytochemicals from Artemisia Vestita Against Osteoarthritis. Iranian Journal of Chemistry and Chemical Engineering. 2025; 44(3): 687-706.
31.    Liao Y, Wang J, Jaehnig EJ, Shi Z, Zhang B. WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic acids research. 2019; 47(W1): W199-W205. https://doi.org/10.1093/nar/gkz401
32.    Gondokesumo ME, Muslikh FA, Pratama RR, Ma’arif B, Aryantini D, Alrayan R, Luthfiana D. The potential of 12 flavonoid compounds as alzheimer's inhibitors through an in silico approach. Journal of Medicinal and Pharmaceutical Chemistry Research (JMPCR). 2024; 6(1): 50-61. https://doi.org/10.48309/jmpcr.2024.182761
33.    Elsaman T, Awadalla MKA, Mohamed MS, Eltayib EM, Mohamed MA. Identification of Microbial-Based Natural Products as Potential CYP51 Inhibitors for Eumycetoma Treatment: Insights from Molecular Docking, MM-GBSA Calculations, ADMET Analysis, and Molecular Dynamics Simulations. Pharmaceuticals. 2025; 18(4): 598. https://doi.org/10.3390/ph18040598
34.    Odhiambo DO, Omosa LK, Njagi EC, Kithure JG, Wekesa EN. In-silico Pharmacokinetics ADME/Tox Analysis of phytochemicals from genus Dracaena for their therapeutic potential. Scientific African. 2025; e02796. https://doi.org/10.1016/j.sciaf.2025.e02796
35.    Muslikh FA, Pratama RR, Ma'arif B, Purwitasari N. In silico study of flavonoid compounds in inhibiting RNA-dependent RNA polymerase (RdRp) as an Antivirus for COVID-19. Journal of Islamic Pharmacy. 2023; 8(1): 49-55. https://doi.org/10.18860/jip.v8i1.21722
36.    Ma'arif B, Aminullah M, Saidah NL, Muslikh FA, Rahmawati A, Indrawijaya YYA, ... and Taek MM. Prediction of antiosteoporosis activity of thirty-nine phytoestrogen compounds in estrogen receptor-dependent manner through in silico approach. Tropical Journal of Natural Product Research. 2021; 5(10): 1727-1734. http://www.doi.org/10.26538/tjnpr/v1i4.5
37.    Sardar H. Drug like potential of Daidzein using SwissADME prediction: In silico Approaches. Phytonutrients. 2023; 02: 02-08. http://dx.doi.org/10.62368/pn.vi.18
38.    Atakishiyeva GT, Qajar AM, Babayeva GV, Mukhtarova SH, Zeynalli NR, Ahmedova NE, Shikhaliyev NQ. Biological new targets prediction and adme profiling of 1, 1-dichlordiazodienes on the basis of o-nitrobenzoic aldehyde. New Materials, Compounds and Applications. 2023; 7(2): 84-92.
39.    Igwe OU, Anyaogu MU, Otuokere IE. Chemical, Antioxidant and Antibacterial Assessment of Clove (Syzygium aromaticum) Seed Extract and in-silico Pharmacokinetic Exploration of the Prominent Compounds. Journal of Applied Sciences and Environmental Management. 2024; 28(7): 1935-1943. https://doi.org/10.4314/jasem.v28i7.2
40.    Patadiya N, and Vaghela V. Design, in-silico ADME Study and molecular docking study of novel quinoline-4-on derivatives as Factor Xa Inhibitor as Potential anti-coagulating agents. Asian Journal of Pharmaceutical Research. 2022; 12(3): 207-211. https://doi.org/10.52711/2231-5691.2022.00034
41.    Pawar S, Kulkarni C, Gadade P, Pujari S, Kakade S, Rohane SH, Redasani VK. Molecular docking using different tools. Asian Journal of Pharmaceutical Research. 2023; 13(4): 292-296. https://doi.org/10.52711/2231-5691.2023.00053
42.    Dighe AS, and Tajamulhaq AE. An overview of molecular docking. Asian Journal of Pharmaceutical Research. 2024; 14(3): 336-340. https://doi.org/10.52711/2231-5691.2024.00053
43.    Pawar SS, and Rohane SH. Review on discovery studio: An important tool for molecular docking. Asian J. Research Chem. 2021; 14(1): 86-88. https://doi.org/10.5958/0974-4150.2021.00014.6
44.    Patil NS, and Rohane SH. Organization of Swiss Dock: in study of computational and molecular docking study. Asian Journal of Research in Chemistry. 2021; 14(2): 145-148. https://doi.org/10.5958/0974-4150.2021.00027.4
45.    Pawar RP, and Rohane SH. Role of autodock vina in PyRx molecular docking. Asian Journal of Research in Chemistry. 2021; 14(2): 132-134. https://doi.org/10.5958/0974-4150.2021.00024.9
46.    Zou J, Zhang W, Hu J, Zhou X, Zhang B. DockEM: an enhanced method for atomic-scale protein–ligand docking refinement leveraging low-to-medium resolution cryo-EM density maps. Briefings in Bioinformatics. 2025; 26(2): bbaf091. https://doi.org/10.1093/bib/bbaf091
47.    Liu Y, Grimm M, Dai WT, Hou MC, Xiao ZX, Cao Y. CB-Dock: a web server for cavity detection-guided protein–ligand blind docking. Acta Pharmacologica Sinica. 2020; 41(1): 138-144. https://doi.org/10.1038/s41401-019-0228-6
48.    Liu Y, Yang X, Gan J, Chen S, Xiao ZX, Cao Y. CB-Dock2: improved protein–ligand blind docking by integrating cavity detection, docking and homologous template fitting. Nucleic acids research. 2022; 50(W1): W159-W164. https://doi.org/10.1093/nar/gkac394
49.    Rivera ZAA, Talubo NDD, Cabrera HS. Network Pharmacology and Molecular Docking Analysis of Morinda citrifolia Fruit Metabolites Suggest Anxiety Modulation through Glutamatergic Pathways. Life. 2024; 14(9): 1182. https://doi.org/10.3390/life14091182
50.    Sharma AD, Kaur I, Chauhan A. Molecular docking studies of principal components and in vitro inhibitory activities of Rosmarinus officinalis essential oil against Aspergillus flavus, Aspergillus fumigatus and Mucor indicus. Phytomedicine Plus. 2023; 3(4): 100493. https://doi.org/10.1016/j.phyplu.2023.100493
51.    Snak EVP, Wande IN, Mahartini NN. Severe Falciparum Malaria with Multiple Complications in Sanglah Hospital Denpasar. Indonesian Journal of Clinical Pathology and Medical Laboratory. 2023; 29(2): 206-210. https://doi.org/10.24293/ijcpml.v29i2.1830
52.    Yam XY, and Preiser PR. Host immune evasion strategies of malaria blood stage parasite. Molecular BioSystems. 2017; 13(12): 2498-2508. https://doi.org/10.1039/c7mb00502d
53.    Verma AK, and Mina PR. Recent advances in antimalarial drug discovery—challenges and opportunities. An Overview of Tropical Diseases. 2021; 39. http://dx.doi.org/10.5772/intechopen.97401
54.    Fikadu M, and Ashenafi E. Malaria: an overview. Infection and Drug Resistance. 2023; 16: 3339-3347. https://doi.org/10.2147/IDR.S405668
55.    Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014; 41(4): 529-542. https://doi.org/10.1016/j.immuni.2014.10.004
56.    Choi YS, Eto D, Yang JA, Lao C, Crotty S. Cutting edge: STAT1 is required for IL-6–mediated Bcl6 induction for early follicular helper cell differentiation. The Journal of Immunology. 2013; 190(7): 3049-3053. https://doi.org/10.4049/jimmunol.1203032
57.    Ma CS, Avery DT, Chan A, Batten M, Bustamante J, Boisson-Dupuis S, ... and Tangye SG. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood, The Journal of the American Society of Hematology. 2012; 119(17): 3997-4008. https://doi.org/10.1182/blood-2011-11-392985
58.    Ray JP, Marshall HD, Laidlaw BJ, Staron MM, Kaech SM, Craft J. Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. Immunity. 2014; 40(3): 367-377. https://doi.org/10.1016/j.immuni.2014.02.005
59.    Carpio VH, Aussenac F, Puebla-Clark L, Wilson KD, Villarino AV, Dent AL, Stephens R. T helper plasticity is orchestrated by STAT3, Bcl6, and Blimp-1 balancing pathology and protection in malaria. Iscience. 2020; 23(7). https://doi.org/10.1016/j.isci.2020.101310
60.    Forte B, Ottilie S, Plater A, Campo B, Dechering KJ, Gamo FJ, ... and Gilbert IH. Prioritization of molecular targets for antimalarial drug discovery. ACS infectious diseases. 2021; 7(10): 2764-2776. https://doi.org/10.1021/acsinfecdis.1c00322
61.    Wiser MF. The digestive vacuole of the malaria parasite: a specialized lysosome. Pathogens. 2024; 13(3): 182. https://doi.org/10.3390/pathogens13030182
62.    Mishra M, Singh V, Singh S. Structural insights into key Plasmodium proteases as therapeutic drug targets. Frontiers in Microbiology. 2019; 10: 394. https://doi.org/10.3389/fmicb.2019.00394
63.    Ettari R, Previti S, Di Chio C, Zappalà M. Falcipain-2 and falcipain-3 inhibitors as promising antimalarial agents. Current Medicinal Chemistry. 2021; 28(15): 3010-3031. https://doi.org/10.2174/0929867327666200730215316
64.    Arwansyah A, Rahmawati S, Nuryanti S, Yusuf Y, Arif AR. Molecular investigation on active compounds in papaya leaves (Carica papaya Linn) as anti-malaria using network pharmacology, molecular docking, clustering-based analysis and molecular dynamics simulation. Phytomedicine Plus. 2025; 5(1): 100713. https://doi.org/10.1016/j.phyplu.2024.100713
65.    Liu M, Amodu AS, Pitts S, Patrickson J, Hibbert JM, Battle M, ... Stiles JK. Heme mediated STAT3 activation in severe malaria. PLoS One. 2012; 7(3): e34280.
66.    Trasia RF, Prathita YA, Utami LI. Current review in malaria pathogenesis and host immune response. International Journal of Medicine and Public Health. 2024; 1(1): 1-10.
67.    Popa GL, Popa MI. Recent advances in understanding the inflammatory response in malaria: a review of the dual role of cytokines. Journal of immunology research. 2021; 2021(1): 7785180. https://doi.org/10.1155/2021/7785180
68.    Ramdhani D, and Kusuma SAF. Antihyperlipidemic Docking Study of Cycloartenol Compound From Musa balbisiana Colla With Some Targets Related With Hyperlipidemia. World Journal of Pharmaceutical Research. 2021; 10(9): 80-87.
69.    Paul S, Mandal K, Santra MK, Bhattacharya AK. Cyclopropane Containing Triterpenoids, Cycloartenone, and Cycloartenol: Isolation, Chemical Transformations, and Anticancer Studies. Chemistry Select. 2025; 10(9): e202403698. https://doi.org/10.1002/slct.202403698

Recomonded Articles:

Research Journal of Pharmacy and Technology (RJPT) is an international, peer-reviewed, multidisciplinary journal.... Read more >>>

RNI: CHHENG00387/33/1/2008-TC                     
DOI: 10.52711/0974-360X 

1.3
2021CiteScore
 
56th percentile
Powered by  Scopus


SCImago Journal & Country Rank

Journal Policies & Information


Recent Articles




Tags


Not Available