Pharmacophore Modeling, Molecular Docking, and ADMET Approach for Identification of Anti-Cancer Agents Targeting the C-Jun N-Terminal Kinase (JNK) Protein

Nur Ayu Ramadanti; Linda Erlina; Rafika Indah Paramita; Aryo Tedjo; Fadillah Fadillah; Surya Dwira

doi:10.24036/eksakta/vol24-iss01/391

EKSAKTA: Berkala Ilmiah Bidang MIPA

Open Access

Pharmacophore Modeling, Molecular Docking, and ADMET Approach for Identification of Anti-Cancer Agents Targeting the C-Jun N-Terminal Kinase (JNK) Protein

Nur Ayu Ramadanti ¹

, Linda Erlina ²

, Rafika Indah Paramita ²

, Aryo Tedjo ²

, Fadillah Fadillah ²

, Surya Dwira ²

¹ Masterâ€™s Programme in Biomedical Science, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

² Department of Medical Chemistry, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

Published 2023-03-30

Vol. 24 No. 01 (2023) PAGES 99-111

DOI 10.24036/eksakta/vol24-iss01/391

Views / Downloads 686 331

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Abstract

One of the most prevalent cancers in Indonesia is breast cancer, based on Indonesia's pathological-based registration.Â Â Â Breast cancer is a complex, heterogeneous disease classified into hormone-receptor-positive, human epidermal growth factor receptor-2 overexpressing (HER2+) and triple-negative breast cancer (TNBC) based on histological features. Patients with HR+, HER2- Early Breast Cancer (EBC) do not experience recurrence or recurrence for a long time with currently available standard therapy [11]. However, up to 30% of patients with high-risk clinical and/or pathological features may experience a relapse in the first few years. This results in the need for research and development regarding updates in medicine both in terms of treatment and targets and drug compounds used. The c-Jun N-terminal kinase (JNK) protein functions in signaling and influences the apoptotic pathway as well as cancer cell survival. In this study, an insilico screening experiment of inhibitory compounds was carried out on the JNK protein receptor target by screening compounds and molecular docking of compounds for breast cancer therapy.Two novel herbal compounds, Mangostin and ent-Copalyl Dyphospate, have the potential to be turned into medicines that may cause apoptosis through JNK protein targets according to an in-silico-based molecular simulation technique

References

1

Alqahtani, S. (2017). In silico ADME-Tox modeling: progress and prospects. Expert Opinion on Drug Metabolism and Toxicology, 13(11), 1147â€“1158.

2

Ashenden, M., Van Weverwijk, A., Murugaesu, N., Fearns, A., Campbell, J., Gao, Q., Iravani, M., & Isacke, C. M. (2017). An in vivo functional screen identifies JNK signaling as a modulator of chemotherapeutic response in breast cancer. Molecular Cancer Therapeutics, 16(9), 1967â€“1978.

3

Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394â€“424.

4

Chen, G. L., Fan, M. X., Wu, J. L., Li, N., & Guo, M. Q. (2019). Antioxidant and anti-inflammatory properties of flavonoids from lotus plumule. Food Chemistry, 277(November 2018), 706â€“712.

5

Fasoulakis, Z., Koutras, A., Syllaios, A., Schizas, D., Garmpis, N., Diakosavvas, M., Angelou, K., Tsatsaris, G., Pagkalos, A., Ntounis, T., & Kontomanolis, E. N. (2021). Breast cancer apoptosis and the therapeutic role of luteolin. Chirurgia (Romania), 116(2), 170â€“177.

6

Gajjar, K. A., & Gajjar, A. K. (2020). Combiphore (Structure and Ligand Based Pharmacophore) - Approach for the Design of GPR40 Modulators in the Management of Diabetes. Current Drug Discovery Technologies, 17(2), 233â€“247.

7

Jade, D. D., Pandey, R., Kumar, R., & Gupta, D. (2022). Ligand-based pharmacophore modeling of TNF-Î± to design novel inhibitors using virtual screening and molecular dynamics. Journal of Biomolecular Structure & Dynamics, 40(4), 1702â€“1718.

8

Kalyaanamoorthy, S., & Chen, Y. P. P. (2011). Structure-based drug design to augment hit discovery. Drug Discovery Today, 16(17â€“18), 831â€“839.

9

Katsura, C., Ogunmwonyi, I., Kankam, H. K., & Saha, S. (2022). Breast cancer: presentation, investigation and management. British Journal of Hospital Medicine (London, England : 2005), 83(2), 1â€“7.

10

Kutlushina, A., Khakimova, A., Madzhidov, T., & Polishchuk, P. (2018). Ligand-Based Pharmacophore Modeling Using Novel 3D Pharmacophore Signatures. Molecules (Basel, Switzerland), 23(12).

11

Li, Q., Yan, X. T., Zhao, L. C., En, S., He, Y. F., Liu, W. C., Wang, Z., Li, X. D., Jiang, S., & Li, W. (2020). Î±-Mangostin, a Dietary Xanthone, Exerts Protective Effects on Cisplatin-Induced enal Injury via PI3K/Akt and JNK Signaling Pathways in HEK293 Cells. ACS Omega, 5(32), 19960â€“19967.

12

Liu, X., Zhu, F., Ma, X. H., Shi, Z., Yang, S. Y., Wei, Y. Q., & Chen, Y. Z. (2013). Send Orders of Reprints at reprints@benthamscience.net Predicting Targeted Polypharmacology for Drug Repositioning and Multi-Target Drug Discovery. Current Medicinal Chemistry, 20, 1646â€“1661.

13

Langeswaran, K., Jeyaraman, J., Jegannath Babu, R., Biswas, A., & Dhurgadevi, K. R. (2019). Identifying dual leucine zipper kinase (DLK) inhibitors using e-pharamacophore screening and molecular docking. Journal of Receptors and Signal Transduction, 39(2), 99â€“105.

14

Pinzi, L., & Rastelli, G. (2019). Metode berbasis struktur bergantung pada informasi yang diperoleh dari pengetahuan tentang struktur 3D target yang menarik, dan mereka memungkinkan database peringkat molekul sesuai dengan struktur dan komplementaritas elektronik ligan ke target tertentu. Igms in Drug Discovery. InternatInPinzi, L., & Rastelli, G. (2019). Molecular Docking: Shifting Paradional Journal of Molecular Sciences, 20(18).

15

Provenzano, E., Ulaner, G. A., & Chin, S.-F. (2018). Molecular Classification of Breast Cancer. PET Clinics, 13(3), 325â€“338.

16

Rakha, E. A., & Green, A. R. (2017). Molecular classification of breast cancer: what the pathologist needs to know. Pathology, 49(2), 111â€“119.

17

Ashenden, M., Van Weverwijk, A., Murugaesu, N., Fearns, A., Campbell, J., Gao, Q., Iravani, M., & Isacke, C. M. (2017). An in vivo functional screen identifies JNK signaling as a modulator of chemotherapeutic response in breast cancer. Molecular Cancer Therapeutics, 16(9), 1967â€“1978.

18

Nagini, S. (2017). Breast Cancer: Current Molecular Therapeutic Targets and New Players. Anti-Cancer Agents in Medicinal Chemistry, 17(2), 152â€“163.

19

Changchien, C.-Y., Chang, H.-H., Dai, M.-S., Tsai, W.-C., Tsai, H.-C., Wang, C.-Y., Shen, M.-S., Cheng, L.-T., Lee, H.-S., Chen, Y., & Tsai, C.-L. (2021). Distinct JNK/VEGFR signaling on angiogenesis of breast cancer-associated pleural fluid based on hormone receptor status. Cancer Science, 112(2), 781â€“791.

20

Prinz, E., Aviram, S., & Aronheim, A. (2018). WDR62 mediates TNFÎ±-dependent JNK activation via TRAF2-MLK3 axis. Molecular Biology of the Cell, 29(20), 2470â€“2480.

21

Pernas, S., & Tolaney, S. M. (2022). Clinical trial data and emerging strategies: HER2-positive breast cancer. Breast Cancer Research and Treatment, 193(2), 281â€“291.

22

Takada, M., & Toi, M. (2020). Neoadjuvant treatment for HER2-positive breast cancer. Chinese Clinical Oncology, 9(3), 32.

23

Meenakumari, K., & Bupesh, G. (2020). Molecular docking of C-Jun-N-Terminal Kinase (Jnk) with amino-pyrimidine derivatives. Bioinformation, 16(6), 462â€“467.

24

Middleton, G., Fletcher, P., Popat, S., Savage, J., Summers, Y., Greystoke, A., Gilligan, D., Cave, J., Oâ€™Rourke, N., Brewster, A., Toy, E., Spicer, J., Jain, P., Dangoor, A., Mackean, M., Forster, M., Farley, A., Wherton, D., Mehmi, M., â€¦ Billingham, L. (2020). The National Lung Matrix Trial of personalized therapy in lung cancer. Nature, 583(7818), 807â€“812.

25

Momenimovahed, Z., & Salehiniya, H. (2019). Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer: Targets and Therapy, 11, 151â€“164.

26

Nguyen, T. Q., Aumont-Nicaise, M., Andreani, J., Velours, C., Chenon, M., Vilela, F., Geneste, C., Varela, P. F., Llinas, P., & MÃ©nÃ©trey, J. (2018). Characterization of the binding mode of JNK-interacting protein 1 (JIP1) to kinesin-light chain 1 (KLC1). The Journal of Biological Chemistry, 293(36), 13946â€“13960.

27

Nusantoro, Y. R., & Fadlan, A. (2020). Analisis Sifat Mirip Obat, Prediksi ADMET, dan Penambatan Molekular Isatinil-2-Aminobenzoilhidrazon dan kompleks logam transisi Co(II), Ni(II), Cu(II), Zn(II) Terhadap BCL2-XL. Akta Kimia Indonesia, 5(2), 114.

28

Opo, F. A. D. M., Rahman, M. M., Ahammad, F., Ahmed, I., Bhuiyan, M. A., & Asiri, A. M. (2021). Structure based pharmacophore modeling, virtual screening, molecular docking and ADMET approaches for identification of natural anti-cancer agents targeting XIAP protein. Scientific Reports, 11(1), 1â€“18.

29

Panigroro, S., Hernowo, B. S., & Purwanto, H. (2019). Panduan Penatalaksanaan Kanker Payudara (Breast Cancer Treatment Guideline). Jurnal Kesehatan Masyarakat, 4(4), 1â€“50.

30

Rakha, E. A., Reis-Filho, J. S., Baehner, F., Dabbs, D. J., Decker, T., Eusebi, V., Fox, S. B., Ichihara, S., Jacquemier, J., Lakhani, S. R., Palacios, J., Richardson, A. L., Schnitt, S. J., Schmitt, F. C., Tan, P.-H., Tse, G. M., Badve, S., & Ellis, I. O. (2010). Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Research : BCR, 12(4), 207.

31

Ross, E., Swallow, J., Kerr, A., Chekar, C. K., & Cunningham-Burley, S. (2021). Diagnostic layering: Patient accounts of breast cancer classification in the molecular era. Social Science & Medicine, 278, 113965.

32

Lamba, M., Munjal, G., Gigras, Y., & Kumar, M. (2023). Breast cancer prediction and categorization in the molecular era of histologic grade. Multimedia Tools and Applications, 1-20.

33

Rohilla, A., Khare, G., & Tyagi, A. K. (2017). Virtual Screening, pharmacophore development and structure based similarity search to identify inhibitors against IdeR, a transcription factor of Mycobacterium tuberculosis. Scientific Reports, 7(1), 1â€“14.

34

Singh, S., Goswami, N., Tyagi, A. K., & Khare, G. (2019). Unraveling the role of the transcriptional regulator VirS in low pHâ€“induced responses of Mycobacterium tuberculosis and identification of VirS inhibitors. Journal of Biological Chemistry, 294(26), 10055-10075.

35

Brzostek, A., PÅ‚ociÅ„ski, P., Minias, A., Ciszewska, A., GÄ…sior, F., PaweÅ‚czyk, J., ... & Dziadek, J. (2021). Dissecting the RecA-(In) dependent response to mitomycin C in Mycobacterium tuberculosis using transcriptional profiling and proteomics analyses. Cells, 10(5), 1168.

36

Schaller, D., Å ribar, D., Noonan, T., Deng, L., Nguyen, T. N., Pach, S., Machalz, D., Bermudez, M., & Wolber, G. (2020). Next generation 3D pharmacophore modeling. Wiley Interdisciplinary Reviews: Computational Molecular Science, 10(4), 1â€“20.

37

Shi, J., Li, J., Li, J., Li, R., Wu, X., Gao, F., Zou, L., Mak, W. W. S., Fu, C., Zhang, J., & Leung, G. P. H. (2021). Synergistic breast cancer suppression efficacy of doxorubicin by combination with glycyrrhetinic acid as an angiogenesis inhibitor. Phytomedicine, 81(November 2020), 153408.

38

Solikhah, S., Promthet, S., & Hurst, C. (2019). Awareness Level about Breast Cancer Risk Factors, Barriers, Attitude and Breast Cancer Screening among Indonesian Women. Asian Pacific Journal of Cancer Prevention : APJCP, 20(3), 877â€“884.

39

Tagliafico, A. S., Piana, M., Schenone, D., Lai, R., Massone, A. M., & Houssami, N. (2020). Overview of radiomics in breast cancer diagnosis and prognostication. Breast, 49, 74â€“80.

40

Tsang, J. Y. S., & Tse, G. M. (2020). Molecular Classification of Breast Cancer. Advances in Anatomic Pathology, 27(1), 27â€“35.

41

Al-Thoubaity, F. K. (2020). Molecular classification of breast cancer: A retrospective cohort study. Annals of medicine and surgery, 49, 44-48.

42

Rakha, E. A., & Green, A. R. (2017). Molecular classification of breast cancer: what the pathologist needs to know. Pathology, 49(2), 111-119.

43

Wu, Q., Wu, W., Jacevic, V., Franca, T. C. C., Wang, X., & Kuca, K. (2020). Selective inhibitors for JNK signalling: a potential targeted therapy in cancer. Journal of Enzyme Inhibition and Medicinal Chemistry, 35(1), 574â€“583.

44

Zhang, Y., Wang, Y., Xing, J., Wan, J., Wang, X., Zhang, J., Wang, X., Li, Z., & Zhang, M. (2020). Copalyl Diphosphate Synthase Mutation Improved Salt Tolerance in Maize (Zea mays. L) via Enhancing Vacuolar Na+ Sequestration and Maintaining ROS Homeostasis. Frontiers in Plant Science, 11(May), 1â€“15.

45

Zhu, X., Li, J., Ning, H., Yuan, Z., Zhong, Y., Wu, S., & Zeng, J. Z. (2021). Î±-Mangostin Induces Apoptosis and Inhibits Metastasis of Breast Cancer Cells via Regulating RXRÎ±-AKT Signaling Pathway. Frontiers in Pharmacology, 12(August), 1â€“11.