Targeting AKT1 in Oral Cancer: In Silico Insights from Chrysanthemum morifolium Phytoconstituents

Fawwaz Sirajuddin Haris, Salsabila Tri Damayanti, Prisca Valensia, Nabila Meysun Mardiana, Syarif Rahmat Aziz, Fasya Assyla Anjani, Dhania Novitasari

Abstract


Oral squamous cell carcinoma (OSCC) is a prevalent type of oral cancer known to be closely associated with the activation of the PI3K/AKT/mTOR pathway, particularly the AKT1 protein, which plays a critical role in cancer cell proliferation, migration, and survival. This study aims to evaluate the potential of bioactive compounds from Chrysanthemum flowers (Chrysanthemum morifolium) as AKT1 inhibitor candidates using an in silico approach. A total of 30 bioactive compounds were then analyzed through drug-likeness assessment based on Lipinski’s rule, ADME-Tox prediction, pharmacophore screening, and molecular docking against the AKT1 receptor (PDB ID: 3CQW). The results revealed that 17 out of 30 compounds complied with Lipinski’s rule, while all compounds were successfully identified as hits in the best pharmacophore model with an AUC value of 0.70. Molecular docking for the compounds then were validated using the protein’s original ligand, yielding a reliable RMSD value of 0.76 Å. Apigenin-7-O-glucuronide exhibited the highest pharmacophore fit score of 34.42, whereas apigenin-7-O-glucoside demonstrated the best binding affinity with a binding energy of -10.29 kcal/mol, which was lower than the reference compound Capivasertib (-9.52 kcal/mol). However, based on the integration of all evaluated parameters, apigenin exhibited the most balanced profile, characterized by compliance with Lipinski’s rule, favorable ADME-Tox properties, a pharmacophore fit score of 34.22, and the lowest inhibition constant value of 0.00193 µM. Collectively, apigenin holds strong potential as a promising AKT1 inhibitor candidate for the development of OSCC therapeutics and warrants further investigation through in vitro and in vivo studies.

Keywords


Oral squamous cell carcinoma, AKT1, Chrysanthemum morifolium, pharmacophore screening, molecular docking

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References


[1] International Agency for Research on Cancer (IARC), Indonesia Fact Sheet, GLOBOCAN 2022, 2024.

[2] M. Alonso-Juarranz, M. Mascaraque, E. Carrasco, T. Gracia-Cazaña, O. De La Sen, Y. Gilaberte, and F. Falahat, "The distinctive features behind the aggressiveness of oral and cutaneous squamous cell carcinomas," Cancers, vol. 15, no. 12, pp. 3227, 2023.

[3] Y. Tan, Z. Wang, M. Xu, B. Li, Z. Huang, S. Qin, and C. Huang, "Oral squamous cell carcinomas: State of the field and emerging directions," International Journal of Oral Science, vol. 15, no. 1, pp. 44, 2023.

[4] D. M. Ferreira, T. J. Neves, L. G. C. A. Lima, F. A. Alves, and M. D. Begnami, "Prognostic implications of the phosphatidylinositol 3-kinase/Akt signaling pathway in oral squamous cell carcinoma: Over expression of p-mTOR indicates an adverse prognosis," Applied Cancer Research, vol. 37, pp. 41, 2017.

[5] S. Lakshminarayana, D. Augustine, R. S. Rao, S. Patil, K. H. Awan, S. S. Venkatesiah, and K. Prasad, "Molecular pathways of oral cancer that predict prognosis and survival: A systematic review," Journal of Carcinogenesis, vol. 17, pp. 7, 2018.

[6] P. Rajendran, R. Sekar, P. S. Dhayasankar, E. M. Ali, S. A. Abdelsalam, S. Balaraman, and B. M. Abdallah, "PI3K/AKT signaling pathway mediated autophagy in oral carcinoma: A comprehensive review," International Journal of Medical Sciences, vol. 21, no. 6, pp. 1165–1186, 2024.

[7] L. R. P. Queiroz, F. V. C. Barcellos, A. L. O. Costa, F. R. O. Melo, M. R. P. Lacerda, and A. L. Z. Guimaraes, "Molecular Docking and Molecules of Interest for Oral Squamous Cell Carcinoma: A Systematic Review," Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, vol. 37, pp. 1159–1166, 2025.

[8] A. Peng, L. Lin, M. Zhao, and B. Sun, "Classification of edible chrysanthemums based on phenolic profiles and mechanisms underlying the protective effects of characteristic phenolics on oxidatively damaged erythrocyte," Food Research International, vol. 123, pp. 64–74, 2019.

[9] W. T. Chia, K. Y. Chen, C. Y. Yang, C. C. Hsieh, C. H. Tsao, C. K. Lin, and Y. W. Chen, "Okanin inhibits cell growth and induces apoptosis and pyroptosis in oral cancer," Cancers, vol. 16, no. 18, pp. 3195, 2024.

[10] E. Primavera, D. Palazzotti, M. L. Barreca, and A. Astolfi, “Computer-Aided Identification of Kinase-Targeted Small Molecules for Cancer: A Review on AKT Protein,” Pharmaceuticals, vol. 16, no. 7, pp. 993, July 2023. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC10384952/. [Accessed Aug. 28, 2026].

[11] G. Voelcker, “Oxazaphosphorine cytostatics,” Anti-Cancer Drugs, vol. 30, no. 5, pp. 435–440, June 2019. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC9698716/. [Accessed Aug. 28, 2026].

[12] S. Safe, A. Jayaraman, R. S. Chapkin, M. Howard, K. Mohankumar, and R. Shrestha, “Flavonoids: structure–function and mechanisms of action and opportunities for drug development,” Toxicological Research, vol. 37, no. 2, pp. 147–162, Jan. 2021. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC8007671/. [Accessed Aug. 28, 2026].

[13] M. Aulia, F. Rosani, T. N. Romadhona, L. G. Kinanti, K. Gabriel, A. Rusdin, and D. Novitasari, "Catechin from Avocado Seed (Persea americana Mill.) Potentially Targets Estrogen Receptor-Alpha: Computational-Based Analysis," Biota: Jurnal Ilmiah Ilmu-Ilmu Hayati, vol. 10, no. 3, pp. 222–232, Oct. 2025

[14] N. A. Duran-Iturbide, B. I. Diaz-Eufracio, and J. L. Medina-Franco, "In Silico ADME/Tox Profiling of Natural Products: A Focus on BIOFACQUIM," ACS Omega, vol. 5, no. 1, pp. 16076–16084, 2020.

[15] J. S. L. Yu and W. Cui, "Proliferation, survival and metabolism: The role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination," Development, vol. 143, pp. 3050–3060, 2016.

[16] C. A. Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney, "Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings," Advanced Drug Delivery Reviews, vol. 46, no. 1–3, pp. 3–26, 2009.

[17] H. Zhang, Y. I. Hassan, R. Liu, L. Mats, C. Yang, C. Liu, and R. Tsao, "Molecular Mechanisms Underlying the Absorption of Aglycone and Glycosidic Flavonoids in a Caco-2 BBe1 Cell Model," ACS Omega, vol. 5, pp. 10782–10793, 2020

[18] P. B. Mohite and D. D. Pawar, "In silico Prioritization of Some Tetrazole Chalcones for Anticonvulsant Activity," International Journal of PharmTech Research, vol. 12, no. 2, pp. 155–161, 2019.

[19] A. A. Elaine, A. Nisa, N. Tahara, D. Q. Aini, and Z. Syahriar, "In Silico Study of Mangosteen Fruit (Garcinia mangostana L.) as Pancreatic Anticancer Against AKT Kinase," Indonesian Journal of Biological Pharmacy, vol. 3, no. 1, pp. 19–32, 2023.

[20] Al-Qassabi, S. P. F. Tan, P. Phonboon, A. Galetin, A. Rostami-Hodjegan, and D. Scotcher, "Facing the facts of altered plasma protein binding: Do current models correctly predict changes in fraction unbound in special populations?," Journal of Pharmaceutical Sciences, vol. 113, no. 6, pp. 1664–1673, 2024.

[21] A. A. Abdelwahab, M. A. Elattar, and S. A. Fawzi, "Advancing ADMET prediction for major CYP450 isoforms: Graph-based models, limitations, and future directions," BioMedical Engineering OnLine, vol. 24, no. 1, pp. 93, 2025.

[22] M. Noga and K. Jurowski, "ADME of Bromo-DragonFLY as an example of a new psychoactive substance (NPS): Application of in silico methods for prediction: Absorption, distribution, metabolism and excretion," Scientific Reports, vol. 15, no. 1, pp. 22949, 2025.

[23] S. W. Sari, A. Wilapangga, A. N. Sari, and S. Astriani, "Studi In Silico Potensi Farmakokinetik Dua Senyawa Dari Tanaman Kenaf (Hibiscus cannabinus L.) Untuk Prediksi Toksisitas," Jurnal Bina Cipta Husada, vol. 19, no. 2, pp. 70–79, 2023.

[24] Muchtaridi, M. Syahidah, H. N. Subarnas, A. Yusuf, M. Bryant, S. D. and Langer, T, “Molecular Docking and 3D-Pharmacophore Modeling to Study the Interactions of Chalcone Derivatives with Estrogen Receptor Alpha,” Pharmaceuticals, vol. 10, no. 4, pp. 81, 2017. [Online]. Available: https://doi.org/10.3390/ph10040081. [Accessed Aug. 28, 2026].

[25] D. T. Wilujeng, M. Fatekurohman, and I. M. Tirta, "Analisis Risiko Kredit Perbankan Menggunakan Algoritma K-Nearest Neighbor dan Nearest Weighted K-Nearest Neighbor," Indonesian Journal of Applied Statistics, vol. 5, no. 2, pp. 142–148, 2023.

[26] F. Stanzione, I. Gianreco, and J. C. Cole, "Use of Molecular Docking Computational Tools in Drug Discovery," Progress in Medicinal Chemistry, vol. 60, pp. 273–343, 2021.

[27] J. Li, A. Fu, and L. Zhang, "An Overview of Scoring Functions Used for Protein-Ligand Interactions in Molecular Docking," Interdisciplinary Sciences: Computational Life Sciences, vol. 11, no. 2, pp. 320–328, 2019

[28] T. Z. A. D. Putri, R. P. Findrayani, M. Isrul, and N. Lolok, "Studi Molecular Docking Senyawa Kimia dari Herba Putri Malu (Mimosa pudica) Terhadap Inhibisi Enzim A-Glukosidase Sebagai Antidiabetes Melitus," Jurnal Pharmacia Mandala Waluya, vol. 3, no. 4, pp. 225–233, 2024.

[29] K. Petsri, M. Yokoya, S. Racha, S. Thongsom, C. Thepthanee, B. Innets, Z. Z. Ei, D. Hotta, H. Zou, and P. Chanvorachote, “Novel synthetic derivative of renieramycin T right-half analog induces apoptosis and inhibits cancer stem cells via targeting the Akt signal in lung cancer cells”, International Journal of Molecular Sciences, vol. 24, no. 6, pp. 5345, 2023.

[30] Allinger, N. L., “Conformational Analysis. 130. MM2. Hydrocarbon Force Field Utilizing V1 and V2 Torsional Terms”, vol. 99, no. 25, pp. 8127-8134, 1977.

[31] Das, A., Sahu, P., and Ali, S. M., “Molecular Dynamics Simulation or the Calibration of the OPLS Force Field Using DFT Derived Partial Charges for the Screening of Alkyl Phosphate Ligands by Studying Structure, Dynamics, and Thermodynamics”, Journal of Chemical and Engineering Data, vol. 62, 2280-2295, 2017.

[32] Bikadi, Z. and Hazai, E., “Application of the PM6 Semi-empirical Method to Modeling Proteins Enhances Docking Accuracy of AutoDock”, Journal of Cheminformatics, vol. 1, no. 15, 2009/

[33] Hassanejad-Asl, B., Pooresmaeil, F., Azadi, S., Najafi, A., Esmaeili, A., Bagheri-Mohammadi, S., and Kazemi, B., “Computational Drug Discovery of Potential 5α-reductase Phytochemical Inhibitors and Hair Growth Promotion Using in silico Techniques”, Frontiers in Bioinformatics, vol. 5, pp. 1570101, 2025.

[34] Babiyana, S., Balachandran, V., Thirughanasambantham, N., Viji, A., Narayana, B., and Salian, V. V., “Synthesis, Theoretical, Spectroscopic Profiles, Topological and Structure-Based Biological Activities of 2-[3-(4-chlorophenyl0)]-5-(4-(isopropyl)phenyl)-4,5-dihydro-1 H-pyrazol-1-yl-4-(4-methylphenyl)-1,3-thiazole as a Newly Synthesis of Anti-Inflammatory Agent”, Discover Chemistry, vol. 2, no. 273, 2025

[35] L.O. Anifowose, O.K. Paimo, F.N. Adegboyega, O.M. Ogunyemi, R.O. Akano, S.F. Hammad, and M.A. Ghazy, "Molecular docking appraisal of Dysphania ambrosioides phytochemicals as potential inhibitor of a key triple-negative breast cancer driver gene," In Silico Pharmacology, vol. 11, no. 1, p. 15, 2023. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC10267046/. [Accessed Aug. 28, 2026].

[36] M. Berga, K. Logviss, L. Lauberte, A. Paulausks, and V. Mohylyuk, "Flavonoids in the Spotlight: Bridging the Gap between Physicochemical Properties and Formulation Strategies," Pharmaceuticals, vol. 16, no. 10, p. 1407, 2023. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC10610233/. [Accessed Aug. 28, 2026].

[37] Mahajan, P., Wadhwa, B., Barik, M. R., Malik, F., and Nargotra, A., “Combining Ligand- and Structure-Based in silico Methods for the Identification of Natural Product-Based Inhibitors of AKT1”, Molecular Diversity, vol. 24, pp. 45-60, 2020.

[38] Addies, M., Ballard, P., Buttar, D., Crafter, C., Currie, G., Davies, B. R., Debreczeni, J., Dry, H., Dudley, P., Greenwood, R., Johnson, P. D., Kettle, J. G., Lane, C., Lamont, G., Leach, A., Luke, R. W. A., Morris, J., Ogilvie, D., Page, K., Pass, M., Pearson, S., and Ruston, L., “Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of AKT Kinases”, Journal of Medicinal Chemistry, vol. 56, no. 5, pp.2059-2073, 2013.

[39] Borges, P. H. O., Pedreiro, S., Baptista, S. J., Geraldes, C. F. G. C., Batista, M. T., Silva, M. M. C., and Figueirinha, A., “Inhibition of α-glucosidase by Flavonoids of Cymbopogon citratus (DC) Stapf”, Journal of Ethnopharmacology, vol. 280, pp.114470, 2021.

[40] Kotik, M., Kulik, N., and Valentová, K, “Flavonoids as Aglycones in Retaining Glycosidase-Catalyzed Reactions: Prospects for Green Chemistry”, Journal of Agricultural and Food Chemistry, vol. 71, pp. 14890-14910, 2023.




DOI: https://doi.org/10.18860/al.v14i2.44929

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