IN SILICO ANALYSIS OF COX2 AND TNF-Α FOR THERAPEUTIC DRUG DISCOVERY IN ULCERATIVE COLITIS
Main Article Content
Keywords
In silico analysis, COX2, TNF-α, Drug discovery, Ulcerative colitis, Molecular docking
Abstract
Ulcerative colitis poses a significant challenge in the medical field, demanding innovative therapeutic strategies. In this study, we conducted an In Silico analysis focusing on cyclooxygenase-2 (COX2) and tumor necrosis factor-alpha (TNF-α) to explore potential therapeutic avenues for UC. Utilizing molecular docking simulations, we investigated the binding affinities of natural compounds, namely phyllembin and ursolic acid, with COX2 and TNF-α. Our results revealed notable interactions between phyllembin and COX2, with binding affinities of -6.6 kcal/mol, and TNF-α with an affinity of -4.9 kcal/mol. Similarly, ursolic acid displayed strong binding affinities of -7.5 kcal/mol with COX2 and -3.5 kcal/mol with TNF-α. Molecular docking simulations unraveled the active sites within the COX2 and TNF-α, along with the directing binding sites of these natural compounds of importance to chalk out the potential mechanisms for their pharmacological and therapeutic implications. The pharmacological analysis of these compounds further approved their distinctness, drug like behaviour, and prospects of pharmacotherapeutic efficacy. This study underscores the significance of in silico as a promising tool for expediting the drug discovery for UC to facilitate the atomic level specific binding of these natural compounds with key inflammatory mediators to rationally design the therapy for the attenuation of the inflammation in UC.
References
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29. Mesquida, M., Drawnel, F., & Fauser, S. (2019). The role of inflammation in diabetic eye disease. Paper presented at the Seminars in Immunopathology.
30. Michalak, M. (2022). Plant-derived antioxidants: Significance in skin health and the ageing process. International journal of molecular sciences, 23(2), 585.
31. Muhammad, M. (2019). Tumor necrosis factor alpha: a major cytokine of brain neuroinflammation. Cytokines, 861231.
32. Müller, N. (2019). COX-2 inhibitors, aspirin, and other potential anti-inflammatory treatments for psychiatric disorders. Frontiers in Psychiatry, 10, 375.
33. Musyuni, P., Sharma, R., & Aggarwal, G. (2023). Optimizing drug discovery: An opportunity and application with reverse translational research. Health Sciences Review, 6, 100074.
34. Ndeke, A. N. (2022). Study of the Effect of Acetaminophen on Reproduction Using the Female Mouse Model. University of Nairobi,
35. Nema, N. K., Khamborkar, S. D., Sarojam, S., Chacko, B. K., & Jacob, V. (2023). Phytoconstituents from Mother Nature against SARS-CoV-2/COVID-19. Medicinal Plants, Phytomedicines and Traditional Herbal Remedies for Drug Discovery and Development against COVID-19, 1.
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41. Serreli, G., & Deiana, M. (2019). In vivo formed metabolites of polyphenols and their biological efficacy. Food & Function, 10(11), 6999-7021.
42. Sethi, J. K., & Hotamisligil, G. S. (2021). Metabolic messengers: tumour necrosis factor. Nature metabolism, 3(10), 1302-1312.
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45. Singh, G., Kaur, J., Kaur, M., Singh, P., & Bhatti, R. (2020). Anti-nociceptive and anti-inflammatory effect of imperatorin: evidences for involvement of COX-2, iNOS, NFκB and inflammatory cytokines. International Journal of Neuroscience, 130(2), 176-185.
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47. Sippl, W., & Ntie-Kang, F. (2020). Natural Products as Modulators of Sirtuins. Molecules (Basel, Switzerland), 25(14).
48. Surur, A. S., Schulig, L., & Link, A. (2019). Interconnection of sulfides and sulfoxides in medicinal chemistry. Archiv der Pharmazie, 352(1), 1800248.
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50. Thirunavukkarasu, M. K., Suriya, U., Rungrotmongkol, T., & Karuppasamy, R. (2021). In silico screening of available drugs targeting non-small cell lung cancer targets: A drug repurposing approach. Pharmaceutics, 14(1), 59.
51. Tong, W., Chen, X., Song, X., Chen, Y., Jia, R., Zou, Y., . . . Liang, X. (2020). Resveratrol inhibits LPS‑induced inflammation through suppressing the signaling cascades of TLR4‑NF‑κB/MAPKs/IRF3. Experimental and Therapeutic Medicine, 19(3), 1824-1834.
52. Ullrich, K. A.-M., Schulze, L. L., Paap, E.-M., Müller, T. M., Neurath, M. F., & Zundler, S. (2020). Immunology of IL-12: An update on functional activities and implications for disease. EXCLI journal, 19, 1563.
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56. Wang, S., Lee, D. Y.-w., Shang, Y., Liao, J., Cao, X., Xie, L., . . . Dai, R. (2021). The bioactive alkaloids identified from Cortex Phellodendri ameliorate benign prostatic hyperplasia via LOX-5/COX-2 pathways. Phytomedicine, 93, 153813.
57. Zadka, Ł., Grybowski, D. J., & Dzięgiel, P. (2020). Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance. Cellular Oncology, 43, 539-575.
58. Zhai, L., Huang, T., Xiao, H.-t., Wu, P.-g., Lin, C.-y., Ning, Z.-w., . . . Wong, H. L. X. (2020). Berberine Suppresses colonic inflammation in dextran sulfate sodium–induced murine colitis through inhibition of cytosolic phospholipase A2 activity. Frontiers in pharmacology, 11, 576496.
59. Zhang, W., Huai, Y., Miao, Z., Qian, A., & Wang, Y. (2019). Systems pharmacology for investigation of the mechanisms of action of traditional Chinese medicine in drug discovery. Frontiers in pharmacology, 10, 743.
2. Akhter, S., Irfan, H. M., Alamgeer, Jahan, S., Shahzad, M., & Latif, M. B. (2022). Nerolidol: a potential approach in rheumatoid arthritis through reduction of TNF-α, IL-1β, IL-6, NF-kB, COX-2 and antioxidant effect in CFA-induced arthritic model. Inflammopharmacology, 30(2), 537-548.
3. Amoroso, C., Perillo, F., Strati, F., Fantini, M., Caprioli, F., & Facciotti, F. (2020). The role of gut microbiota biomodulators on mucosal immunity and intestinal inflammation. Cells, 9(5), 1234.
4. Brogi, S., Ramalho, T. C., Kuca, K., Medina-Franco, J. L., & Valko, M. (2020). In silico methods for drug design and discovery. In (Vol. 8, pp. 612): Frontiers Media SA.
5. Cui, J., & Jia, J. (2021). Natural COX-2 inhibitors as promising anti-inflammatory agents: an update. Current Medicinal Chemistry, 28(18), 3622-3646.
6. da Silva Hage-Melim, L. I., Federico, L. B., de Oliveira, N. K. S., Francisco, V. C. C., Correia, L. C., de Lima, H. B., . . . Francischini, I. A. G. (2020). Virtual screening, ADME/Tox predictions and the drug repurposing concept for future use of old drugs against the COVID-19. Life Sciences, 256, 117963.
7. dos Santos Nascimento, I. J., & da Silva-Júnior, E. F. (2022). TNF-α Inhibitors from natural compounds: An overview, CADD approaches, and their exploration for anti-inflammatory agents. Combinatorial Chemistry & High Throughput Screening, 25(14), 2317-2340.
8. Gawehn, E. (2022). Leveraging self-organizing maps with convolutional neural networks for virtual chemical library screening. ETH Zurich,
9. Green, E. D., Gunter, C., Biesecker, L. G., Di Francesco, V., Easter, C. L., Feingold, E. A., . . . Pavan, W. J. (2020). Strategic vision for improving human health at The Forefront of Genomics. Nature, 586(7831), 683-692.
10. Habtemariam, S. (2023). The Molecular Pharmacology of Phloretin: Anti-Inflammatory Mechanisms of Action. Biomedicines, 11(1), 143.
11. Hassan, M., Awan, F. M., Naz, A., deAndrés-Galiana, E. J., Alvarez, O., Cernea, A., . . . Kloczkowski, A. (2022). Innovations in genomics and big data analytics for personalized medicine and health care: A review. International journal of molecular sciences, 23(9), 4645.
12. Hausmann, J. S. (2019). Targeting cytokines to treat autoinflammatory diseases. Clinical Immunology, 206, 23-32.
13. Hu, T.-Y., Ju, J.-M., Mo, L.-H., Ma, L., Hu, W.-H., You, R.-R., . . . Qiu, S.-Q. (2019). Anti-inflammation action of xanthones from Swertia chirayita by regulating COX-2/NF-κB/MAPKs/Akt signaling pathways in RAW 264.7 macrophage cells. Phytomedicine, 55, 214-221.
14. Jenny, J., & B Kumar, P. (2021). Dihydroxy berberine from Tinospora cordifolia: in silico evidences for the mechanism of anti-inflammatory action through dual inhibition of Lipoxygenase and Cyclooxygenase. Indian Journal of Biochemistry and Biophysics (IJBB), 58(3), 244-252.
15. Kar, S., Roy, K., & Leszczynski, J. (2022). In silico tools and software to predict ADMET of new drug candidates. In in silico methods for predicting drug toxicity (pp. 85-115): Springer.
16. Karaman Mayack, B., Sippl, W., & Ntie-Kang, F. (2020). Natural products as modulators of sirtuins. Molecules, 25(14), 3287.
17. Khan, M. (2022). Insulin resistance reversal potential of selected medicinal plants derived leads against TNF-a induced insulin resistance.
18. Khan, M. S., Mehmood, B., Yousafi, Q., Bibi, S., Fazal, S., Saleem, S., . . . Kamal, M. A. (2021). Molecular docking studies reveal rhein from rhubarb (rheum rhabarbarum) as a putative inhibitor of ATP-binding cassette super-family G member 2. Medicinal Chemistry, 17(3), 273-288.
19. Konda, S. R. (2023). Optimizing Computer Architectures for High-Performance Drug Discovery Workflows. INTERNATIONAL JOURNAL OF COMPUTER SCIENCE AND TECHNOLOGY, 7(3), 243-258.
20. Kővári, B., Báthori, Á., Friedman, M. S., & Lauwers, G. Y. (2022). Histologic diagnosis of inflammatory bowel diseases. Advances in Anatomic Pathology, 29(1), 48-61.
21. Kucharzik, T., Koletzko, S., Kannengiesser, K., & Dignass, A. (2020). Ulcerative colitis—Diagnostic and therapeutic algorithms. Deutsches Ärzteblatt International, 117(33-34), 564.
22. Le Berre, C., Ananthakrishnan, A. N., Danese, S., Singh, S., & Peyrin-Biroulet, L. (2020). Ulcerative colitis and Crohn’s disease have similar burden and goals for treatment. Clinical Gastroenterology and Hepatology, 18(1), 14-23.
23. Li, G., Fang, Y., Ma, Y., Dawa, Y., Wang, Q., Gan, J., & Dang, J. (2022). Screening and Isolation of Potential Anti-Inflammatory Compounds from Saxifraga atrata via Affinity Ultrafiltration-HPLC and Multi-Target Molecular Docking Analyses. Nutrients, 14(12), 2405.
24. Lippert, J., Burghaus, R., Edginton, A., Frechen, S., Karlsson, M., Kovar, A., . . . Ramusovic, S. (2019). Open systems pharmacology community—an open access, open source, open science approach to modeling and simulation in pharmaceutical sciences. CPT: pharmacometrics & systems pharmacology, 8(12), 878.
25. Liu, C., Ma, Y., Zhao, J., Nussinov, R., Zhang, Y.-C., Cheng, F., & Zhang, Z.-K. (2020). Computational network biology: data, models, and applications. Physics Reports, 846, 1-66.
26. Liu, Z., Roberts, R. A., Lal-Nag, M., Chen, X., Huang, R., & Tong, W. (2021). AI-based language models powering drug discovery and development. Drug Discovery Today, 26(11), 2593-2607.
27. McCabe, W. A. (2020). The role of PNPLA3 in the development and progression of chronic liver injury. UCL (University College London),
28. Menzel, A., Samouda, H., Dohet, F., Loap, S., Ellulu, M. S., & Bohn, T. (2021). Common and novel markers for measuring inflammation and oxidative stress ex vivo in research and clinical practice—which to use regarding disease outcomes? Antioxidants, 10(3), 414.
29. Mesquida, M., Drawnel, F., & Fauser, S. (2019). The role of inflammation in diabetic eye disease. Paper presented at the Seminars in Immunopathology.
30. Michalak, M. (2022). Plant-derived antioxidants: Significance in skin health and the ageing process. International journal of molecular sciences, 23(2), 585.
31. Muhammad, M. (2019). Tumor necrosis factor alpha: a major cytokine of brain neuroinflammation. Cytokines, 861231.
32. Müller, N. (2019). COX-2 inhibitors, aspirin, and other potential anti-inflammatory treatments for psychiatric disorders. Frontiers in Psychiatry, 10, 375.
33. Musyuni, P., Sharma, R., & Aggarwal, G. (2023). Optimizing drug discovery: An opportunity and application with reverse translational research. Health Sciences Review, 6, 100074.
34. Ndeke, A. N. (2022). Study of the Effect of Acetaminophen on Reproduction Using the Female Mouse Model. University of Nairobi,
35. Nema, N. K., Khamborkar, S. D., Sarojam, S., Chacko, B. K., & Jacob, V. (2023). Phytoconstituents from Mother Nature against SARS-CoV-2/COVID-19. Medicinal Plants, Phytomedicines and Traditional Herbal Remedies for Drug Discovery and Development against COVID-19, 1.
36. Pechanova, O., Dayar, E., & Cebova, M. (2020). Therapeutic potential of polyphenols-loaded polymeric nanoparticles in cardiovascular system. Molecules, 25(15), 3322.
37. Pisoschi, A. M., Iordache, F., Stanca, L., Cimpeanu, C., Furnaris, F., Geicu, O. I., . . . Serban, A. I. (2023). Comprehensive and critical view on the anti-inflammatory and immunomodulatory role of natural phenolic antioxidants. European Journal of Medicinal Chemistry, 116075.
38. Pu, L., Naderi, M., Liu, T., Wu, H.-C., Mukhopadhyay, S., & Brylinski, M. (2019). e toxpred: A machine learning-based approach to estimate the toxicity of drug candidates. BMC Pharmacology and Toxicology, 20, 1-15.
39. Rafe, T., Shawon, P. A., Salem, L., Chowdhury, N. I., Kabir, F., Bin Zahur, S. M., . . . Sagor, M. A. (2019). Preventive role of resveratrol against inflammatory cytokines and related diseases. Current pharmaceutical design, 25(12), 1345-1371.
40. Savva, L., & Georgiades, S. N. (2021). Recent developments in small-molecule ligands of medicinal relevance for harnessing the anticancer potential of G-quadruplexes. Molecules, 26(4), 841.
41. Serreli, G., & Deiana, M. (2019). In vivo formed metabolites of polyphenols and their biological efficacy. Food & Function, 10(11), 6999-7021.
42. Sethi, J. K., & Hotamisligil, G. S. (2021). Metabolic messengers: tumour necrosis factor. Nature metabolism, 3(10), 1302-1312.
43. Shaker, B., Ahmad, S., Lee, J., Jung, C., & Na, D. (2021). In silico methods and tools for drug discovery. Computers in biology and medicine, 137, 104851.
44. Sharif, P. M., Jabbari, P., Razi, S., Keshavarz-Fathi, M., & Rezaei, N. (2020). Importance of TNF-alpha and its alterations in the development of cancers. Cytokine, 130, 155066.
45. Singh, G., Kaur, J., Kaur, M., Singh, P., & Bhatti, R. (2020). Anti-nociceptive and anti-inflammatory effect of imperatorin: evidences for involvement of COX-2, iNOS, NFκB and inflammatory cytokines. International Journal of Neuroscience, 130(2), 176-185.
46. Singh, V., Johnson, K., Yin, J., Lee, S., Lin, R., Yu, H., . . . Donowitz, M. (2022). Chronic inflammation in ulcerative colitis causes long-term changes in goblet cell function. Cellular and Molecular Gastroenterology and Hepatology, 13(1), 219-232.
47. Sippl, W., & Ntie-Kang, F. (2020). Natural Products as Modulators of Sirtuins. Molecules (Basel, Switzerland), 25(14).
48. Surur, A. S., Schulig, L., & Link, A. (2019). Interconnection of sulfides and sulfoxides in medicinal chemistry. Archiv der Pharmazie, 352(1), 1800248.
49. Taku, K., Britta, S., Chen, W. S., Ferrante, M., Shen, B., Bernstein, C. N., . . . Toshifumi, H. (2020). Ulcerative colitis (primer). Nature Reviews: Disease Primers, 6(1).
50. Thirunavukkarasu, M. K., Suriya, U., Rungrotmongkol, T., & Karuppasamy, R. (2021). In silico screening of available drugs targeting non-small cell lung cancer targets: A drug repurposing approach. Pharmaceutics, 14(1), 59.
51. Tong, W., Chen, X., Song, X., Chen, Y., Jia, R., Zou, Y., . . . Liang, X. (2020). Resveratrol inhibits LPS‑induced inflammation through suppressing the signaling cascades of TLR4‑NF‑κB/MAPKs/IRF3. Experimental and Therapeutic Medicine, 19(3), 1824-1834.
52. Ullrich, K. A.-M., Schulze, L. L., Paap, E.-M., Müller, T. M., Neurath, M. F., & Zundler, S. (2020). Immunology of IL-12: An update on functional activities and implications for disease. EXCLI journal, 19, 1563.
53. Valdés-Tresanco, M. S., Valdés-Tresanco, M. E., Valiente, P. A., & Moreno, E. (2020). AMDock: a versatile graphical tool for assisting molecular docking with Autodock Vina and Autodock4. Biology direct, 15(1), 1-12.
54. Vieira, T. F., & Sousa, S. F. (2019). Comparing AutoDock and Vina in ligand/decoy discrimination for virtual screening. Applied Sciences, 9(21), 4538.
55. Vo, A. H., Van Vleet, T. R., Gupta, R. R., Liguori, M. J., & Rao, M. S. (2019). An overview of machine learning and big data for drug toxicity evaluation. Chemical research in toxicology, 33(1), 20-37.
56. Wang, S., Lee, D. Y.-w., Shang, Y., Liao, J., Cao, X., Xie, L., . . . Dai, R. (2021). The bioactive alkaloids identified from Cortex Phellodendri ameliorate benign prostatic hyperplasia via LOX-5/COX-2 pathways. Phytomedicine, 93, 153813.
57. Zadka, Ł., Grybowski, D. J., & Dzięgiel, P. (2020). Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance. Cellular Oncology, 43, 539-575.
58. Zhai, L., Huang, T., Xiao, H.-t., Wu, P.-g., Lin, C.-y., Ning, Z.-w., . . . Wong, H. L. X. (2020). Berberine Suppresses colonic inflammation in dextran sulfate sodium–induced murine colitis through inhibition of cytosolic phospholipase A2 activity. Frontiers in pharmacology, 11, 576496.
59. Zhang, W., Huai, Y., Miao, Z., Qian, A., & Wang, Y. (2019). Systems pharmacology for investigation of the mechanisms of action of traditional Chinese medicine in drug discovery. Frontiers in pharmacology, 10, 743.
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Mar 18, 2024
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Pari Gul, Malik Ihsan Ullah Khan, Sadaf Ajmal, Kulsoom Baloch, Basira Akhtar, & Shaista Anjum. (2024). IN SILICO ANALYSIS OF COX2 AND TNF-Α FOR THERAPEUTIC DRUG DISCOVERY IN ULCERATIVE COLITIS. Journal of Population Therapeutics and Clinical Pharmacology, 31(3), 932 - 946. https://doi.org/10.53555/jptcp.v30i17.5052
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.
Author Biographies
Pari Gul
Institute of Molecular Biology and Biotechnology, University of Lahore, Pakistan.
Malik Ihsan Ullah Khan
Institute of Molecular Biology and Biotechnology, University of Lahore, Pakistan
Sadaf Ajmal
Department of Genetics, University of Karachi, Pakistan
Kulsoom Baloch
Institute of Biochemistry, University Of Balochistan, Pakistan
Basira Akhtar
Department of Botany, University of Balochistan, Pakistan.
Shaista Anjum
Department of Botany, University of Balochistan, Pakistan.
How to Cite
Pari Gul, Malik Ihsan Ullah Khan, Sadaf Ajmal, Kulsoom Baloch, Basira Akhtar, & Shaista Anjum. (2024). IN SILICO ANALYSIS OF COX2 AND TNF-Α FOR THERAPEUTIC DRUG DISCOVERY IN ULCERATIVE COLITIS. Journal of Population Therapeutics and Clinical Pharmacology, 31(3), 932 - 946. https://doi.org/10.53555/jptcp.v30i17.5052