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MOLECULAR DOCKING STUDIES OF COX INHIBITORS ON WILD-TYPE RAS

Yıl 2022, Cilt: 46 Sayı: 1, 23 - 34, 29.01.2022

Dilan Konyar Hayati Okur Zehra Arslan

https://doi.org/10.33483/jfpau.1008048

Öz

Objective: In addition to its role in the formation mechanism of inflammation, the binding potential of COX inhibitors, which can inhibit tumorogenesis by induce apoptosis, has been explored by molecular docking studies on wild-type RAS enzyme.
Material and Method: KRAS enzyme (PDB ID: 4OBE), which consists is obtained by the x-ray crystallization method, was chosed considering the resolution. The 2D structures of ligand molecules were drawn in the ChemDraw 19.1. The MOE 2020 program was used to form the docking studies.
Result and Discussion: As a result of docking studies, it has been understood that the presence of aromatic structures in 3a and 3b ligand molecules is critical for ligand-receptor interaction. it has been understood that there must be a certain distance between the carbonyl group and the nonpolar part of the molecule for the molecule to bind to the receptor site with a high affinity. In the following stages, more effective anticancer drug molecules can be obtained by design molecules with an appropriate diameter and length, having functional groups containing the suitable electron donor or acceptor.

Anahtar Kelimeler

RAS COX inhibitors docking MOE binding affinity

Kaynakça

  • 1. Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., Chakravarty, D., Daian, F., Gao, Q., Bailey, M. H., Liang, W. W., Foltz, S. M., Shmulevich, I., Ding, L., Heins, Z., Marino, M. C. (2018). Oncogenic signaling pathways in the cancer genome atlas. Cell, 173(2), 321-337. [CrossRef]
  • 2. Harvey, J.J. (1964). An unidentified virus which causes the rapid production of tumours in mice. Nature, 204, 1104-1109. [CrossRef]
  • 3. Kirsten, W.H., Mayer, L.A. (1967). Morphologic responses to a murine erythroblastosis virus. Journal of the National Cancer Institute, 39(2), 311-335. [CrossRef]
  • 4. Muñoz-Maldonad, C., Zimmer, Y., Medová, M. (2019). A comparative analysis of individual RAS Mutations in Cancer Biology. Frontiers in Oncology, 9, 1088. [CrossRef]
  • 5. Fernández-Medarde, A., Santos, E. (2011). Ras in cancer and developmental diseases. Genes Cancer, 2(3), 344-358. [CrossRef]
  • 6. Prior, I.A., Lewis, P.D., Mattos, C. (2012). A comprehensive survey of Ras mutations in cancer. Cancer Research, 72, 2457-2467. [CrossRef]
  • 7. Forbes, S.A., Bindal, N., Bamford, S., Cole, C., Kok, C.Y., Beare, D. (2011). COSMIC: Mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Research, 39, (Database issue), D945–D950. [CrossRef]
  • 8. Buday, L., Downward, J. (2008). Many faces of Ras activation. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1786, 178-187. [CrossRef]
  • 9. Johnson, L., Greenbaum, D., Cichowski, K., Mercer, K., Murphy, E., Schmitt, E., Bronson, R.T., Umanoff, H., Edelmann, W., Kucherlapati, R., Jacks, T. (1991). K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes&Development, 11(19), 2468-2481. [CrossRef]
  • 10. Ahmed, A.U. (2011). An overview of inflammation: mechanism and consequences, Frontiers in Biology, 6, 274. [CrossRef] 11. Murata, M. (2018). Inflammation and cancer. Environmental Health and Preventive Medicine, 23, 50. [CrossRef]
  • 12. Kraft, M., Djukanovic, R., Wilson, S., Holgate, S.T., Martin, R.J. (1996). Alveolar tissue inflammation in asthma. American Journal of Respiratory and Critical Care Medicine, 154, 1505-1510. [CrossRef]
  • 13. Choy, E.H.S., Panayi, G.S. (2001). Cytokine pathways and joint inflammation in rheumatoid arthritis. New England Journal of Medicine, 344, 907-916. [CrossRef]
  • 14. Glass, C.K., Saijo, K., Winner, B., Marchetto, M.C., Gage, F.H. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell, 140, 918-934. [CrossRef]
  • 15. Hotamisligil, G.S. (2006). Inflammation and metabolic disorders. Nature, 444, 860-867. [CrossRef]
  • 16. Libby, P., Ridker, P.M., Maseri, A. (2002). Inflammation and atherosclerosis. Circulation, 105, 1135-1143. [CrossRef]
  • 17. Scrivo, R., Vasile, M., Bartosiewicz, I., Valesini, G. (2011). Inflammation as “common soil” of the multifactorial diseases, Autoimmunity Reviews, 10(7), 369-374. [CrossRef]
  • 18. Eling, T.E., Thompson, D.C., Foureman, G.L. (1990). Prostaglandin H synthase and xenobiotic oxidation. Annual Review of Pharmacology and Toxicology, 30, 1-45. [CrossRef]
  • 19. Windmill, K.F., McKinnon, R.A., Zhu, X. (1997). The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: functional and localization studies. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 376, 153-160. [CrossRef]
  • 20. Tsujii, M., Kawano, S., Tsuji, S. (1998). Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell, 93, 705-716. [CrossRef]
  • 21. Hernandez, G.L., Volpert, O.V., Iniguez, M.A. (2001). Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. Journal of Experimental Medicine, 193, 607-620. [CrossRef]
  • 22. Seed, M.P., Brown, J.R., Freemantle, C.N. (1997). The inhibition of colon-26 adenocarcinoma development and angiogenesis by topical diclofenac in 2.5% hyaluronan. Cancer Research, 57, 1625-1629.
  • 23. Li, M., Lotan, R., Levin, B. (2000). Aspirin induction of apoptosis in esophageal cancer: a potential for chemoprevention. Cancer Epidemiology, Biomarkers & Prevention, 9, 545-549.
  • 24. Grossman, E.M., Longo, W.E., Panesar, N. (2000). The role of cyclooxygenase enzymes in the growth of human gall bladder cancer cells. Carcinogenesis, 21, 1403-1409. [CrossRef]
  • 25. Petersen, C., Petersen, S. L. (2000). Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor. Clinical Cancer Research, 6, 2513-2520.
  • 26. Nishimura, G., Yanoma, S., Mizuno, H. (1999). A selective cyclooxygenase-2 inhibitor suppresses tumor growth in nude mouse xenografted with human head and neck squamous carcinoma cells. Japanese Cancer Reserch, 90, 1152-1162. [CrossRef]
  • 27. Zhang, G., Tu, C., Zhou, G. (2000). Indomethacin induces apoptosis and inhibits proliferation in chronic myeloid leukemia cells. Leukemia Research, 24, 385-392. [CrossRef]
  • 28. Hida, T., Kozaki, K., Muramatsu, H. (2000). Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clinical Cancer Research, 6, 2006-2011.
  • 29. Yip-Schneider, M.T., Barnard, D.S., Billings, S.D. (2000). Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis, 21, 139–146. [CrossRef]
  • 30. Liu, X.H., Yao, S., Kirschenbaum, A. (1998). NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down-regulates bcl-2 expression in LNCaP cells. Cancer Research, 58, 4245-4249.
  • 31. Waddell, W.R. (1998). Stimulation of apoptosis by sulindac and piroxicam. Clinical Science (London), 95, 385-388.
  • 32. Hunter, J.C., Gurbani, D., Ficarro, S.B., Carrasco, M.A., Lim, S.M. (2014). In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C. The Proceedings of the National Academy of Sciences, 111, 8895-8900. [CrossRef]
  • 33. Sledz, P., Caflisch, A. (2018). Protein structure-based drug design: from docking to molecular dynamics. Current Opinion in Structural Biology, 48, 93-102. [CrossRef]
  • 34. McCarthy, M.J. , Pagba, C.V., Prakash, P., Naji, A.K., Hoeven, D. (2019). Discovery of high-affinity noncovalent allosteric KRAS inhibitors that disrupt effector binding. ACS Omega, 4, 2921-2930. [CrossRef]
  • 35. Wang, Y., Kaiser, C. E., Frett, B., Li, H. (2013). Targeting mutant KRAS for anticancer therapeutics: A review of novel small molecule modulators. Journal of Medicinal Chemistry, 56(13), 5219-5230. [CrossRef]

COX İNHİBİTÖRLERİNİN YABANİ-TİP RAS ENZİMİ ÜZERİNDE MOLEKÜLER DOKİNG ÇALIŞMALARI

Yıl 2022, Cilt: 46 Sayı: 1, 23 - 34, 29.01.2022

Dilan Konyar Hayati Okur Zehra Arslan

https://doi.org/10.33483/jfpau.1008048

Öz

Amaç: Inflamasyon oluşum mekanizmasındaki rolünün yanı sıra apoptoz oluşumunu tetikleyerek tümorogenesisi inhibe edebilen COX inhibitörlerinin yabani-tip RAS enzimi üzerinde moleküler doking çalışmaları ile bağlanma potansiyelleri araştırılmıştır.
Gereç ve Yöntem: X-ışını kristalizasyon yöntemi ile elde edilen KRAS enzimi (PDB kodu: 4OBE) çözünürlük dikkate alınarak seçilmiştir.Ligand moleküllerinin 2 boyutlu yapıları ChemDraw 19.1'de çizilmiştir. Doking çalışmaları için MOE 2020 programı kullanılmıştır.
Sonuç ve Tartışma: Docking çalışmaları sonucunda 3a ve 3b ligand moleküllerinde aromatik yapıların varlığının ligand-reseptör etkileşimi için kritik olduğu anlaşılmıştır. Molekülün reseptör bölgesine yüksek afinite ile bağlanabilmesi için karbonil grubu ile molekülün polar olmayan kısmı arasında belirli bir mesafe olması gerektiği anlaşılmıştır. İlerleyen aşamalarda uygun elektron verici veya alıcı içeren fonksiyonel gruplara sahip uygun çap ve uzunlukta moleküller tasarlanarak daha etkili antikanser ilaç molekülleri elde edilebilir.

Anahtar Kelimeler

RAS COX inhibitors doking MOE bağlanma afinitesi

Kaynakça

  • 1. Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., Chakravarty, D., Daian, F., Gao, Q., Bailey, M. H., Liang, W. W., Foltz, S. M., Shmulevich, I., Ding, L., Heins, Z., Marino, M. C. (2018). Oncogenic signaling pathways in the cancer genome atlas. Cell, 173(2), 321-337. [CrossRef]
  • 2. Harvey, J.J. (1964). An unidentified virus which causes the rapid production of tumours in mice. Nature, 204, 1104-1109. [CrossRef]
  • 3. Kirsten, W.H., Mayer, L.A. (1967). Morphologic responses to a murine erythroblastosis virus. Journal of the National Cancer Institute, 39(2), 311-335. [CrossRef]
  • 4. Muñoz-Maldonad, C., Zimmer, Y., Medová, M. (2019). A comparative analysis of individual RAS Mutations in Cancer Biology. Frontiers in Oncology, 9, 1088. [CrossRef]
  • 5. Fernández-Medarde, A., Santos, E. (2011). Ras in cancer and developmental diseases. Genes Cancer, 2(3), 344-358. [CrossRef]
  • 6. Prior, I.A., Lewis, P.D., Mattos, C. (2012). A comprehensive survey of Ras mutations in cancer. Cancer Research, 72, 2457-2467. [CrossRef]
  • 7. Forbes, S.A., Bindal, N., Bamford, S., Cole, C., Kok, C.Y., Beare, D. (2011). COSMIC: Mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Research, 39, (Database issue), D945–D950. [CrossRef]
  • 8. Buday, L., Downward, J. (2008). Many faces of Ras activation. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1786, 178-187. [CrossRef]
  • 9. Johnson, L., Greenbaum, D., Cichowski, K., Mercer, K., Murphy, E., Schmitt, E., Bronson, R.T., Umanoff, H., Edelmann, W., Kucherlapati, R., Jacks, T. (1991). K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes&Development, 11(19), 2468-2481. [CrossRef]
  • 10. Ahmed, A.U. (2011). An overview of inflammation: mechanism and consequences, Frontiers in Biology, 6, 274. [CrossRef] 11. Murata, M. (2018). Inflammation and cancer. Environmental Health and Preventive Medicine, 23, 50. [CrossRef]
  • 12. Kraft, M., Djukanovic, R., Wilson, S., Holgate, S.T., Martin, R.J. (1996). Alveolar tissue inflammation in asthma. American Journal of Respiratory and Critical Care Medicine, 154, 1505-1510. [CrossRef]
  • 13. Choy, E.H.S., Panayi, G.S. (2001). Cytokine pathways and joint inflammation in rheumatoid arthritis. New England Journal of Medicine, 344, 907-916. [CrossRef]
  • 14. Glass, C.K., Saijo, K., Winner, B., Marchetto, M.C., Gage, F.H. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell, 140, 918-934. [CrossRef]
  • 15. Hotamisligil, G.S. (2006). Inflammation and metabolic disorders. Nature, 444, 860-867. [CrossRef]
  • 16. Libby, P., Ridker, P.M., Maseri, A. (2002). Inflammation and atherosclerosis. Circulation, 105, 1135-1143. [CrossRef]
  • 17. Scrivo, R., Vasile, M., Bartosiewicz, I., Valesini, G. (2011). Inflammation as “common soil” of the multifactorial diseases, Autoimmunity Reviews, 10(7), 369-374. [CrossRef]
  • 18. Eling, T.E., Thompson, D.C., Foureman, G.L. (1990). Prostaglandin H synthase and xenobiotic oxidation. Annual Review of Pharmacology and Toxicology, 30, 1-45. [CrossRef]
  • 19. Windmill, K.F., McKinnon, R.A., Zhu, X. (1997). The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: functional and localization studies. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 376, 153-160. [CrossRef]
  • 20. Tsujii, M., Kawano, S., Tsuji, S. (1998). Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell, 93, 705-716. [CrossRef]
  • 21. Hernandez, G.L., Volpert, O.V., Iniguez, M.A. (2001). Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. Journal of Experimental Medicine, 193, 607-620. [CrossRef]
  • 22. Seed, M.P., Brown, J.R., Freemantle, C.N. (1997). The inhibition of colon-26 adenocarcinoma development and angiogenesis by topical diclofenac in 2.5% hyaluronan. Cancer Research, 57, 1625-1629.
  • 23. Li, M., Lotan, R., Levin, B. (2000). Aspirin induction of apoptosis in esophageal cancer: a potential for chemoprevention. Cancer Epidemiology, Biomarkers & Prevention, 9, 545-549.
  • 24. Grossman, E.M., Longo, W.E., Panesar, N. (2000). The role of cyclooxygenase enzymes in the growth of human gall bladder cancer cells. Carcinogenesis, 21, 1403-1409. [CrossRef]
  • 25. Petersen, C., Petersen, S. L. (2000). Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor. Clinical Cancer Research, 6, 2513-2520.
  • 26. Nishimura, G., Yanoma, S., Mizuno, H. (1999). A selective cyclooxygenase-2 inhibitor suppresses tumor growth in nude mouse xenografted with human head and neck squamous carcinoma cells. Japanese Cancer Reserch, 90, 1152-1162. [CrossRef]
  • 27. Zhang, G., Tu, C., Zhou, G. (2000). Indomethacin induces apoptosis and inhibits proliferation in chronic myeloid leukemia cells. Leukemia Research, 24, 385-392. [CrossRef]
  • 28. Hida, T., Kozaki, K., Muramatsu, H. (2000). Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clinical Cancer Research, 6, 2006-2011.
  • 29. Yip-Schneider, M.T., Barnard, D.S., Billings, S.D. (2000). Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis, 21, 139–146. [CrossRef]
  • 30. Liu, X.H., Yao, S., Kirschenbaum, A. (1998). NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down-regulates bcl-2 expression in LNCaP cells. Cancer Research, 58, 4245-4249.
  • 31. Waddell, W.R. (1998). Stimulation of apoptosis by sulindac and piroxicam. Clinical Science (London), 95, 385-388.
  • 32. Hunter, J.C., Gurbani, D., Ficarro, S.B., Carrasco, M.A., Lim, S.M. (2014). In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C. The Proceedings of the National Academy of Sciences, 111, 8895-8900. [CrossRef]
  • 33. Sledz, P., Caflisch, A. (2018). Protein structure-based drug design: from docking to molecular dynamics. Current Opinion in Structural Biology, 48, 93-102. [CrossRef]
  • 34. McCarthy, M.J. , Pagba, C.V., Prakash, P., Naji, A.K., Hoeven, D. (2019). Discovery of high-affinity noncovalent allosteric KRAS inhibitors that disrupt effector binding. ACS Omega, 4, 2921-2930. [CrossRef]
  • 35. Wang, Y., Kaiser, C. E., Frett, B., Li, H. (2013). Targeting mutant KRAS for anticancer therapeutics: A review of novel small molecule modulators. Journal of Medicinal Chemistry, 56(13), 5219-5230. [CrossRef]
Toplam 34 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Eczacılık ve İlaç Bilimleri
Bölüm Araştırma Makalesi
Yazarlar

Dilan Konyar 0000-0001-7275-1266

Hayati Okur 0000-0001-6807-8208

Zehra Arslan Bu kişi benim 0000-0001-9169-667X

Yayımlanma Tarihi 29 Ocak 2022
Gönderilme Tarihi 11 Ekim 2021
Kabul Tarihi 22 Ekim 2021
Yayımlandığı Sayı Yıl 2022 Cilt: 46 Sayı: 1

Kaynak Göster

APA Konyar, D., Okur, H., & Arslan, Z. (2022). MOLECULAR DOCKING STUDIES OF COX INHIBITORS ON WILD-TYPE RAS. Journal of Faculty of Pharmacy of Ankara University, 46(1), 23-34. https://doi.org/10.33483/jfpau.1008048
AMA Konyar D, Okur H, Arslan Z. MOLECULAR DOCKING STUDIES OF COX INHIBITORS ON WILD-TYPE RAS. Ankara Ecz. Fak. Derg. Ocak 2022;46(1):23-34. doi:10.33483/jfpau.1008048
Chicago Konyar, Dilan, Hayati Okur, ve Zehra Arslan. “MOLECULAR DOCKING STUDIES OF COX INHIBITORS ON WILD-TYPE RAS”. Journal of Faculty of Pharmacy of Ankara University 46, sy. 1 (Ocak 2022): 23-34. https://doi.org/10.33483/jfpau.1008048.
EndNote Konyar D, Okur H, Arslan Z (01 Ocak 2022) MOLECULAR DOCKING STUDIES OF COX INHIBITORS ON WILD-TYPE RAS. Journal of Faculty of Pharmacy of Ankara University 46 1 23–34.
IEEE D. Konyar, H. Okur, ve Z. Arslan, “MOLECULAR DOCKING STUDIES OF COX INHIBITORS ON WILD-TYPE RAS”, Ankara Ecz. Fak. Derg., c. 46, sy. 1, ss. 23–34, 2022, doi: 10.33483/jfpau.1008048.
ISNAD Konyar, Dilan vd. “MOLECULAR DOCKING STUDIES OF COX INHIBITORS ON WILD-TYPE RAS”. Journal of Faculty of Pharmacy of Ankara University 46/1 (Ocak 2022), 23-34. https://doi.org/10.33483/jfpau.1008048.
JAMA Konyar D, Okur H, Arslan Z. MOLECULAR DOCKING STUDIES OF COX INHIBITORS ON WILD-TYPE RAS. Ankara Ecz. Fak. Derg. 2022;46:23–34.
MLA Konyar, Dilan vd. “MOLECULAR DOCKING STUDIES OF COX INHIBITORS ON WILD-TYPE RAS”. Journal of Faculty of Pharmacy of Ankara University, c. 46, sy. 1, 2022, ss. 23-34, doi:10.33483/jfpau.1008048.
Vancouver Konyar D, Okur H, Arslan Z. MOLECULAR DOCKING STUDIES OF COX INHIBITORS ON WILD-TYPE RAS. Ankara Ecz. Fak. Derg. 2022;46(1):23-34.
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