Integration of Network Pharmacology, Molecular Docking, and Molecular Dynamics to Evaluate Calotropis gigantea flowers Bioactive Compounds as Anti-Cervical Cancer Agents
Keywords:
Calotropis gigantea, Cervical Cancer, Network Pharmacology, Molecular Docking, Molecular Dynamics, Quercetin, Kaempferol, AKT1, SRC, Hub Genes.
Abstract
Cervical cancer remains the fourth most prevalent malignancy among women worldwide, presenting a severe health burden particularly in low-resource regions where therapeutic options are limited. This study investigates the anti-cervical cancer potential of bioactive compounds from Calotropis gigantea flowers using an integrated pipeline of network pharmacology, molecular docking, and molecular dynamics simulations. Phytochemical screening identified 31 compounds, which were subjected to ADME profiling; flavonoids such as quercetin and kaempferol exhibited superior drug-likeness and oral bioavailability compared to high-molecular-weight cardenolides.
A systems-level analysis identified 571 common targets between C. gigantea bioactives and cervical cancer. Through protein–protein interaction network analysis, AKT1, EGFR, SRC, and STAT3 were identified as the primary hub genes governing tumor progression. Functional enrichment results indicated that these targets are central to the PI3K-AKT and EGFR-tyrosine kinase inhibitor resistance pathways. Survival analysis further highlighted JUN (HR = 1.7) and EGFR (HR = 1.6) as significant prognostic biomarkers for poor clinical outcomes in cervical cancer patients.
Molecular docking simulations explored the binding orientations of these ligands within the active sites of key proteins. In this study, quercetin and kaempferol demonstrated potent binding affinities for SRC (–9.10 kcal/mol and –8.80 kcal/mol, respectively) and EGFR (–8.90 kcal/mol), interacting with critical residues such as MET-793 and THR-338. Subsequent MD simulations validated the structural stability of these complexes. Notably, the quercetin–SRC complex exhibited a remarkably low eigenvalue (9.14973 × 10⁻⁵) and stabilized fluctuation profiles, indicating high energetic favorability and structural integrity over time. These results suggest that C. gigantea flower bioactives, particularly quercetin and kaempferol, are promising multi-targeted candidates for further therapeutic development.
References
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23. Vivek-Ananth RP, Mohanraj K, Sahoo AK, Samal A. IMPPAT 2.0: An Enhanced and Expanded Phytochemical Atlas of Indian Medicinal Plants. ACS Omega [Internet]. 2023 Feb 23 [cited 2026 Mar];8(9):8827. Available from: https://doi.org/10.1021/acsomega.3c00156
24. Shahzadi Z, Yousaf Z, Anjum İ, Bilal M, Yasin H, Aftab A, et al. Network pharmacology and molecular docking: combined computational approaches to explore the antihypertensive potential of Fabaceae species. Bioresources and Bioprocessing [Internet]. 2024 May 20 [cited 2025 Oct];11(1). Available from: https://doi.org/10.1186/s40643-024-00764-6
25. Sarkar K, Roy P, Panda S, Choudhuri C, Chowdhury M. Ethnomedicinal study on plant resources from sacred groves of Dakshin Dinajpur district, West Bengal, India. Ethnobotany Research and Applications [Internet]. 2023 Mar 13 [cited 2025 Oct];25. Available from: https://doi.org/10.32859/era.25.32.1-35
26. Afees OJ, Arietarhire L, Soremekun O, Olugbogi EA, Aribisala PO, Alege PE, et al. Reporting the Anti-neuroinflammatory Potential of Selected Spondias mombin Flavonoids through Network Pharmacology and Molecular Dynamics Simulations. Research Square (Research Square) [Internet]. 2024 Apr 11 [cited 2025 Sep]; Available from: https://doi.org/10.21203/rs.3.rs-4248639/v1
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28. Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Research [Internet]. 2019 May 1 [cited 2026 Mar];47. Available from: https://doi.org/10.1093/nar/gkz382
29. Islam MM, Sreeharsha N, Alshabrmi FM, Asif AH, Al‐Dhubiab BE, Anwer MdK, et al. From seeds to survival rates: investigating Linum usitatissimum’s potential against ovarian cancer through network pharmacology. Frontiers in Pharmacology [Internet]. 2023 Oct 30 [cited 2025 Sep];14. Available from: https://doi.org/10.3389/fphar.2023.1285258
30. Qian K, Fu D, Jiang B, Wang Y, Tian F, Li S, et al. Mechanism of Hedyotis Diffusa in the Treatment of Cervical Cancer. Frontiers in Pharmacology [Internet]. 2021 Dec 15 [cited 2025 Oct];12. Available from: https://doi.org/10.3389/fphar.2021.808144
31. Janani B, Vijayakumar M, Priya K, Kim JH, Geddawy A, Shahid M, et al. A network-based pharmacological investigation to identify the mechanistic regulatory pathway of andrographolide against colorectal cancer. Frontiers in Pharmacology [Internet]. 2022 Aug 30 [cited 2025 Oct];13. Available from: https://doi.org/10.3389/fphar.2022.967262
32. pisal H, Badhe P, Mali P. Network pharmacology based virtual screening of active constituents of moringa oleifera and the molecular mechanism against breast cancer. Research Square (Research Square) [Internet]. 2024 May 22 [cited 2025 Oct]; Available from: https://doi.org/10.21203/rs.3.rs-4452781/v1
33. Kumar GS, Manivannan R, Nivetha B, Kamalakannan D, Bhuvaneshwari K, Ammu R, et al. Unraveling the Multi-Target Pharmacological Mechanism of Brassica rapa in Diabetes Treatment: Integration of Network Pharmacology and Molecular Docking Approaches. Journal of Drug Delivery and Therapeutics [Internet]. 2023 Apr 15 [cited 2025 Aug];13(4):13. Available from: https://doi.org/10.22270/jddt.v13i4.5783
34. Aarthy M, Muthuramalingam P, Ramesh M, Singh SK. Unraveling the multi-targeted curative potential of bioactive molecules against cervical cancer through integrated omics and systems pharmacology approach. Scientific Reports [Internet]. 2022 Aug 21 [cited 2025 Oct];12(1). Available from: https://doi.org/10.1038/s41598-022-18358-7
35. Wang R, Gao C, Yu M, Song J, Feng Z, Wang R, et al. Mechanistic Prediction and validation of Brevilin A Therapeutic Effects in Lung Cancer. Research Square (Research Square) [Internet]. 2024 Mar 6 [cited 2025 Sep]; Available from: https://doi.org/10.21203/rs.3.rs-3986795/v1
36. El‐Hawary SS, Albalawi MA, Montasser AOS, Ahmed SR, Qasim S, Shati AA, et al. Network pharmacology and molecular docking study for biological pathway detection of cytotoxicity of the yellow jasmine flowers. BMC Complementary Medicine and Therapies [Internet]. 2023 May 20 [cited 2025 Oct];23(1). Available from: https://doi.org/10.1186/s12906-023-03987-w
37. Zhang D, Dong YZ, Lv J, Zhang B, Zhang X, Lin Z. Network pharmacology modeling identifies synergistic interaction of therapeutic and toxicological mechanisms for Tripterygium hypoglaucum Hutch. BMC Complementary Medicine and Therapies [Internet]. 2021 Jan 15 [cited 2025 Oct];21(1). Available from: https://doi.org/10.1186/s12906-021-03210-8
38. Rashid A. Untitled [Internet]. 2024 Mar [cited 2025 Nov]. Available from: https://doi.org/10.55277/researchhub.vq5dnd6h
39. Alblihy A. From desert flora to cancer therapy: systematic exploration of multi-pathway mechanisms using network pharmacology and molecular modeling approaches. Frontiers in Pharmacology [Internet]. 2024 Apr 11 [cited 2025 Oct];15. Available from: https://doi.org/10.3389/fphar.2024.1345415
40. Fan Z, Wang S, Xu C, Yang J, Cui B. Mechanisms of action of Fu Fang Gang Liu liquid in treating condyloma acuminatum by network pharmacology and experimental validation. BMC Complementary Medicine and Therapies [Internet]. 2023 Apr 20 [cited 2025 Oct];23(1). Available from: https://doi.org/10.1186/s12906-023-03960-7
41. Kalsoom A, Altaf A, Sarwar M, Maqbool T, Ashraf MAB, Sattar H, et al. GC–MS analysis, molecular docking, and apoptotic-based cytotoxic effect of Caladium lindenii Madison extracts toward the HeLa cervical cancer cell line. Scientific Reports [Internet]. 2024 Aug 8 [cited 2025 Aug];14(1). Available from: https://doi.org/10.1038/s41598-024-69582-2
42. Dua R, Bhardwaj T, Ahmad I, Somvanshi P. Investigating the potential of Juglans regia phytoconstituents for the treatment of cervical cancer utilizing network biology and molecular docking approach. PLoS ONE [Internet]. 2024 Apr 16 [cited 2025 Oct];19(4). Available from: https://doi.org/10.1371/journal.pone.0287864
2. Caruso G, Wagar MK, Hsu H, Hoegl J, Valzacchi GMR, Fernándes A, et al. Cervical cancer: a new era. 2024 Aug 8 [cited 2025 Nov]; Available from: https://doi.org/10.1136/ijgc-2024-005579
3. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. 2017 Mar 3 [cited 2025 Oct]; Available from: https://doi.org/10.1038/srep42717
4. Alwin D. SwissADME. 2024 Jan 1 [cited 2025 Nov]; Available from: https://doi.org/10.13140/rg.2.2.19938.75202
5. Ying P, Zhu Y. A network pharmacology study on the Cervix Prescription for treatment of Cervical Cancer. 2021 Aug 24 [cited 2025 Oct]; Available from: https://doi.org/10.21203/rs.3.rs-835232/v1
6. Kamau SW, Jepkorir M, Kipkoech G, Lagu IJL, Kanda W, Kibunja S, et al. Antiproliferative activity of Grewia villosa ethyl acetate extract on cervical cancer HeLa cell line: Mechanistic insights through network pharmacology and functional assays approach. 2025 Sep 24 [cited 2025 Sep]; Available from: https://doi.org/10.1371/journal.pone.0331649
7. Ralte L, Sailo H, Kumar R, Khiangte L, Kumar NS, Singh YT. Identification of novel AKT1 inhibitors from Sapria himalayana bioactive compounds using structure-based virtual screening and molecular dynamics simulations. BMC Complementary Medicine and Therapies [Internet]. 2024 Mar 7 [cited 2025 Oct];24(1). Available from: https://doi.org/10.1186/s12906-024-04415-3
8. Hasan MdT, Islam MdR, Islam MdR, Altahan BR, Ahmed K, Bui FM, et al. Systematic approach to identify therapeutic targets and functional pathways for the cervical cancer. 2023 Feb 1 [cited 2025 Oct]; Available from: https://doi.org/10.1186/s43141-023-00469-x
9. Butt SS, Badshah Y, Shabbir M, Rafiq M. Molecular Docking Using Chimera and Autodock Vina Software for Nonbioinformaticians. 2020 Jun 19 [cited 2026 Feb]; Available from: https://doi.org/10.2196/14232
10. Bhattacharya K, Nath BC, Ahmed E, Khanal P, Chanu NR, Deka S, et al. Integration of network pharmacology, molecular docking, and simulations to evaluate phytochemicals from Drymaria cordata against cervical cancer. 2024 Jan 1 [cited 2025 Oct]; Available from: https://doi.org/10.1039/d3ra06297j
11. Mutiah R, Kristanti RA, Maimunah S. Synergistic Effects of Doxorubicin and Cardenolid Glycosides of Calotropis Gigantea Root on Cervical Cancer Hela Cell Line. 2017 Aug 31 [cited 2025 Sep]; Available from: https://doi.org/10.22146/tradmedj.27924
12. Jayalekshmi C, Das NM, Periakaruppan R. Bioactive compounds of Calotropis gigantea for cancer treatment. 2024 Apr 5 [cited 2025 Nov]; Available from: https://doi.org/10.1016/j.oor.2024.100336
13. Schubert M, Bauerschlag D, Muallem MZ, Maass N, Alkatout İ. Challenges in the Diagnosis and Individualized Treatment of Cervical Cancer. Medicina [Internet]. 2023 May 11 [cited 2026 Feb];59(5):925. Available from: https://doi.org/10.3390/medicina59050925
14. Bhat SS, Sindhu R, Prasad SK. A Bioinformatics Approach Towards Plant-Based Anticancer Drug Discovery. In 2024 [cited 2025 Nov]. p. 35. Available from: https://doi.org/10.1201/9781003354437-2
15. Gogoi B, Gogoi D, Silla Y, Kakoti BB, Bhau BS. Network pharmacology-based virtual screening of natural products from Clerodendrum species for identification of novel anti-cancer therapeutics. Molecular BioSystems [Internet]. 2016 Dec 22 [cited 2026 Jan];13(2):406. Available from: https://doi.org/10.1039/c6mb00807k
16. Winitchaikul T, Sawong S, Surangkul D, Srikummool M, Somran J, Pekthong D, et al. Calotropis gigantea stem bark extract induced apoptosis related to ROS and ATP production in colon cancer cells. PLoS ONE [Internet]. 2021 Aug 3 [cited 2025 Sep];16(8). Available from: https://doi.org/10.1371/journal.pone.0254392
17. Sawong S, Pekthong D, Suknoppakit P, Winitchaikul T, Kaewkong W, Somran J, et al. Calotropis gigantea stem bark extracts inhibit liver cancer induced by diethylnitrosamine. Scientific Reports [Internet]. 2022 Jul 15 [cited 2025 Oct];12(1). Available from: https://doi.org/10.1038/s41598-022-16321-0
18. Kharat KR, Kharat AS. The Calotropis Gigantea Methanolic Extract Induces Apoptosis in Human Breast Carcinoma Cells. PubMed [Internet]. 2019 Nov 1 [cited 2025 Nov];44(6):483. Available from: https://pubmed.ncbi.nlm.nih.gov/31875083
19. Kibushi B, Elbasyouni A, Kpordze SW, Hadil S, Hussein O, Soro S, et al. Recent Advances in Alternative Medicine [Internet]. IntechOpen eBooks. IntechOpen; 2023 [cited 2025 Sep]. Available from: https://doi.org/10.5772/intechopen.1000427
20. Elbasyouni A, Kpordze SW, Hussein HS, Soro O, Mulondo S, Nshimirimana J, et al. The Crosstalk between Phytotherapy and Bioinformatics in the Management of Cancer. In: IntechOpen eBooks [Internet]. IntechOpen; 2023 [cited 2025 Oct]. Available from: https://doi.org/10.5772/intechopen.1001958
21. Luo F, Gu J, Chen L, Xu X. Systems pharmacology strategies for anticancer drug discovery based on natural products. Molecular BioSystems [Internet]. 2014 Jan 1 [cited 2025 Nov];10(7):1912. Available from: https://doi.org/10.1039/c4mb00105b
22. Mohanraj K, Karthikeyan BS, Vivek-Ananth RP, Chand R, Aparna SR, Mangalapandi P, et al. IMPPAT: A curated database of Indian Medicinal Plants, Phytochemistry And Therapeutics. Scientific Reports [Internet]. 2018 Mar 6 [cited 2025 Aug];8(1). Available from: https://doi.org/10.1038/s41598-018-22631-z
23. Vivek-Ananth RP, Mohanraj K, Sahoo AK, Samal A. IMPPAT 2.0: An Enhanced and Expanded Phytochemical Atlas of Indian Medicinal Plants. ACS Omega [Internet]. 2023 Feb 23 [cited 2026 Mar];8(9):8827. Available from: https://doi.org/10.1021/acsomega.3c00156
24. Shahzadi Z, Yousaf Z, Anjum İ, Bilal M, Yasin H, Aftab A, et al. Network pharmacology and molecular docking: combined computational approaches to explore the antihypertensive potential of Fabaceae species. Bioresources and Bioprocessing [Internet]. 2024 May 20 [cited 2025 Oct];11(1). Available from: https://doi.org/10.1186/s40643-024-00764-6
25. Sarkar K, Roy P, Panda S, Choudhuri C, Chowdhury M. Ethnomedicinal study on plant resources from sacred groves of Dakshin Dinajpur district, West Bengal, India. Ethnobotany Research and Applications [Internet]. 2023 Mar 13 [cited 2025 Oct];25. Available from: https://doi.org/10.32859/era.25.32.1-35
26. Afees OJ, Arietarhire L, Soremekun O, Olugbogi EA, Aribisala PO, Alege PE, et al. Reporting the Anti-neuroinflammatory Potential of Selected Spondias mombin Flavonoids through Network Pharmacology and Molecular Dynamics Simulations. Research Square (Research Square) [Internet]. 2024 Apr 11 [cited 2025 Sep]; Available from: https://doi.org/10.21203/rs.3.rs-4248639/v1
27. Gfeller D, Grosdidier A, Wirth M, Daina A, Michielin O, Zoete V. SwissTargetPrediction: a web server for target prediction of bioactive small molecules. Nucleic Acids Research [Internet]. 2014 May 3 [cited 2026 Mar];42. Available from: https://doi.org/10.1093/nar/gku293
28. Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Research [Internet]. 2019 May 1 [cited 2026 Mar];47. Available from: https://doi.org/10.1093/nar/gkz382
29. Islam MM, Sreeharsha N, Alshabrmi FM, Asif AH, Al‐Dhubiab BE, Anwer MdK, et al. From seeds to survival rates: investigating Linum usitatissimum’s potential against ovarian cancer through network pharmacology. Frontiers in Pharmacology [Internet]. 2023 Oct 30 [cited 2025 Sep];14. Available from: https://doi.org/10.3389/fphar.2023.1285258
30. Qian K, Fu D, Jiang B, Wang Y, Tian F, Li S, et al. Mechanism of Hedyotis Diffusa in the Treatment of Cervical Cancer. Frontiers in Pharmacology [Internet]. 2021 Dec 15 [cited 2025 Oct];12. Available from: https://doi.org/10.3389/fphar.2021.808144
31. Janani B, Vijayakumar M, Priya K, Kim JH, Geddawy A, Shahid M, et al. A network-based pharmacological investigation to identify the mechanistic regulatory pathway of andrographolide against colorectal cancer. Frontiers in Pharmacology [Internet]. 2022 Aug 30 [cited 2025 Oct];13. Available from: https://doi.org/10.3389/fphar.2022.967262
32. pisal H, Badhe P, Mali P. Network pharmacology based virtual screening of active constituents of moringa oleifera and the molecular mechanism against breast cancer. Research Square (Research Square) [Internet]. 2024 May 22 [cited 2025 Oct]; Available from: https://doi.org/10.21203/rs.3.rs-4452781/v1
33. Kumar GS, Manivannan R, Nivetha B, Kamalakannan D, Bhuvaneshwari K, Ammu R, et al. Unraveling the Multi-Target Pharmacological Mechanism of Brassica rapa in Diabetes Treatment: Integration of Network Pharmacology and Molecular Docking Approaches. Journal of Drug Delivery and Therapeutics [Internet]. 2023 Apr 15 [cited 2025 Aug];13(4):13. Available from: https://doi.org/10.22270/jddt.v13i4.5783
34. Aarthy M, Muthuramalingam P, Ramesh M, Singh SK. Unraveling the multi-targeted curative potential of bioactive molecules against cervical cancer through integrated omics and systems pharmacology approach. Scientific Reports [Internet]. 2022 Aug 21 [cited 2025 Oct];12(1). Available from: https://doi.org/10.1038/s41598-022-18358-7
35. Wang R, Gao C, Yu M, Song J, Feng Z, Wang R, et al. Mechanistic Prediction and validation of Brevilin A Therapeutic Effects in Lung Cancer. Research Square (Research Square) [Internet]. 2024 Mar 6 [cited 2025 Sep]; Available from: https://doi.org/10.21203/rs.3.rs-3986795/v1
36. El‐Hawary SS, Albalawi MA, Montasser AOS, Ahmed SR, Qasim S, Shati AA, et al. Network pharmacology and molecular docking study for biological pathway detection of cytotoxicity of the yellow jasmine flowers. BMC Complementary Medicine and Therapies [Internet]. 2023 May 20 [cited 2025 Oct];23(1). Available from: https://doi.org/10.1186/s12906-023-03987-w
37. Zhang D, Dong YZ, Lv J, Zhang B, Zhang X, Lin Z. Network pharmacology modeling identifies synergistic interaction of therapeutic and toxicological mechanisms for Tripterygium hypoglaucum Hutch. BMC Complementary Medicine and Therapies [Internet]. 2021 Jan 15 [cited 2025 Oct];21(1). Available from: https://doi.org/10.1186/s12906-021-03210-8
38. Rashid A. Untitled [Internet]. 2024 Mar [cited 2025 Nov]. Available from: https://doi.org/10.55277/researchhub.vq5dnd6h
39. Alblihy A. From desert flora to cancer therapy: systematic exploration of multi-pathway mechanisms using network pharmacology and molecular modeling approaches. Frontiers in Pharmacology [Internet]. 2024 Apr 11 [cited 2025 Oct];15. Available from: https://doi.org/10.3389/fphar.2024.1345415
40. Fan Z, Wang S, Xu C, Yang J, Cui B. Mechanisms of action of Fu Fang Gang Liu liquid in treating condyloma acuminatum by network pharmacology and experimental validation. BMC Complementary Medicine and Therapies [Internet]. 2023 Apr 20 [cited 2025 Oct];23(1). Available from: https://doi.org/10.1186/s12906-023-03960-7
41. Kalsoom A, Altaf A, Sarwar M, Maqbool T, Ashraf MAB, Sattar H, et al. GC–MS analysis, molecular docking, and apoptotic-based cytotoxic effect of Caladium lindenii Madison extracts toward the HeLa cervical cancer cell line. Scientific Reports [Internet]. 2024 Aug 8 [cited 2025 Aug];14(1). Available from: https://doi.org/10.1038/s41598-024-69582-2
42. Dua R, Bhardwaj T, Ahmad I, Somvanshi P. Investigating the potential of Juglans regia phytoconstituents for the treatment of cervical cancer utilizing network biology and molecular docking approach. PLoS ONE [Internet]. 2024 Apr 16 [cited 2025 Oct];19(4). Available from: https://doi.org/10.1371/journal.pone.0287864
Published
2024-07-20
How to Cite
Suresh Kumar Gopal, Rakesh Kumar Jat, & Abdul Mannan Khan. (2024). Integration of Network Pharmacology, Molecular Docking, and Molecular Dynamics to Evaluate Calotropis gigantea flowers Bioactive Compounds as Anti-Cervical Cancer Agents. Revista Electronica De Veterinaria, 25(1), 4564 - 4582. https://doi.org/10.69980/redvet.v25i1.2410
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