SİKLOOKSİJENAZ İNHİBİTÖRLERİ OLARAK BAZI 4,5-DİHİDRO-1H-PİRAZOL TÜREVLERİ ÜZERİNDE MOLEKÜLER DOKİNG ÇALIŞMALARI

Yıl 2021, Cilt: 45 Sayı: 3, 565 - 576, 27.09.2021

Begüm Evranos Aksöz

https://doi.org/10.33483/jfpau.989733

Öz

Amaç: Antiinflamatuvar etkileri olduğu düşünülen bazı 4,5-dihidro-1H-pirazol türevlerinin siklooksijenaz 1(COX-1) ve siklooksijenaz 2 (COX-2) enzimleri ile etkileşimlerini incelemek amacıyla bu enzimler üzerinde docking çalışmaları yapılmıştır.

Gereç ve Yöntem: Doking çalışmaları için protein veri bankasından, COX-1 enzimi için (3KK6) ve COX-2 enzimi için (3LN1) seçilmiştir. Ligand ve proteinin yapıları Autodock 1.5.6 kullanılarak hazırlanmıştır. Bağlanma afinitesini belirlemek için AutoDock Vina, doking sonuçlarını analiz etmek ve görüntülemek için ise Discovery Studio 3.5 kullanılmıştır.

Sonuç ve Tartışma: COX-1 ve COX-2 enzimleri üzerine yapılan doking işlemi sonucunda 4,5-dihidro-1H-pirazol türevlerinin her iki enzimle de etkileşime girdiği görüldü. 4,5-Dihidro-1H-pirazol halkasının COX-2 enzimi ile etkileşimde önemli olduğu bulundu. Yapıya hacimli bir grubun dahil edilmesi, COX-1 enzimi ile etkileşimde herhangi bir soruna neden olmazken, COX-2 enzimi ile bazı etkileşimleri ortadan kaldırdı. Enzimlerin inhibisyon özelliklerinin daha iyi aydınlatılabilmesi için bu çalışmanın in vitro ve in vivo COX inhibisyon testleri ile desteklenmesi gerekmektedir.      

Anahtar Kelimeler

Siklooksijenaz 1, siklooksijenaz 2, 4, 5-dihidro-1H-pirazol, inflamasyon, moleküler doking, 4,5-dihidro-1H-pirazol

MOLECULAR DOCKING STUDIES ON SOME 4,5-DIHYDRO-1H-PYRAZOLE DERIVATIVES AS CYCLOOXYGENASE INHIBITORS

Öz

Objective: To examine the interactions of some 4,5-dihydro-1H-pyrazole derivatives, which are thought to have antiinflammatory effects, with cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, docking studies were carried out on these enzymes.

Material and Method: COX-1 enzyme (3KK6) and COX-2 enzyme (3LN1) were selected from the protein data bank for docking studies. The ligand and protein constructs were prepared using Autodock 1.5.6. AutoDock Vina was used to determining the binding affinity, and Discovery Studio 3.5 was utilised to analyse and display the docking results.

Result and Discussion: As a result of the docking process on COX-1 and COX-2 enzymes, 4,5-Dihydro-1H-pyrazole derivatives were observed to interact with both enzymes. The 4,5-dihydro-1H-pyrazole ring was found to be important in its interactions with the COX-2 enzyme. The inclusion of a bulky group in the construct did not cause any problems in interaction with the COX-1 enzyme but eliminated some interactions with the COX-2 enzyme. To better elucidate the inhibition properties of enzymes, this study should be supported by in vitro and in vivo COX inhibition tests.

Anahtar Kelimeler

Cyclooxygenase-1, cyclooxygenase-2, 4, 5-dihydro-1H-pyrazole, inflammation, molecular docking, 4,5-dihydro-1H-pyrazole

Kaynakça

• 1. Fullerton, J., Gilroy, D. (2016). Resolution of inflammation: a new therapeutic frontier. Nature Reviews Drug Discovery, 15, 551-567.
• 2. Mantzanidou, M., Pontiki, E., Hadjipavlou-Litina, D. Pyrazoles and pyrazolines as anti-inflammatory agents (2021). Molecules, 26(11), 3439.
• 3. Turini, M.E., DuBois, R.N. (2002). Cyclooxygenase-2: A therapeutic target. Annual Review of Medicine, 53, 35-57.
• 4. Chandrasekharan, N., Simmons, D.L. (2004). The cyclooxygenases. Genome Biology, 5(9), 241.
• 5. Zarghi, A., Arfaei, S. (2011). Selective COX-2 inhibitors: A review of their structure-activity relationships. Iranian Journal of Pharmaceutical Research, 10(4), 655-683.
• 6. Rouzer, C.A., Marnett L.J. (2009). Cyclooxygenases: structural and functional insights. Journal of Lipid Research, 50, S29-34.
• 7. Carvalho, L.C.R., Ribeiro, D., Seixas, R.S.G.R., Silva, A.M.S., Nave, M., Martins, A.C., Erhardt, S., Fernandes, E., Cabrita, E.J., Marques, M.M.B. (2015). Synthesis and evaluation of new benzimidazole-based COX inhibitors: a naproxen-like interaction detected by STD-NMR. RSC Advances, 5, 49098-49109.
• 8. Ju, Z., Su, M., Hong, J., La Kim, E., Moon, H.R., Chung, H.Y., Kim, S., Jung, J.H. (2019). Design of balanced COX inhibitors based on antiinflammatory and/or COX-2 inhibitory ascidian metabolites. European Journal of Medicinal Chemistry, 180, 86-98.
• 9. Blobaum, A.L., Marnett, L.J. (2007). Structural and functional basis of cyclooxygenase inhibition. Journal of Medicinal Chemistry, 50(7), 1425-1441.
• 10. El-Sayed, M.A., Abdel-Aziz, N.I., Abdel-Aziz, A.A., El-Azab, A.S., ElTahir, K.E. (2012). Synthesis, biological evaluation and molecular modeling study of pyrazole and pyrazoline derivatives as selective COX-2 inhibitors and antiinflammatory agents. Part 2. Bioorganic and Medicinal Chemistry, 20(10), 3306-3316.
• 11. El-Feky, S.A.H., El-Sami, Z.K.A., Osman, N.A., Lashine, J., Kamel, M.A., Thabet, H.K. (2015). Synthesis, molecular docking and antiinflammatory screening of novel quinoline incorporated pyrazole derivatives using the Pfitzinger reaction. Bioorganic Chemistry, 58, 104-116.
• 12. Abdelall, E.K.A., Lamie, P.F., Ali, W.A.M. (2016). Cyclooxygenase-2 and 15-lipoxygenase inhibition, synthesis, antiinflammatory activity and ulcer liability of new celecoxib analogues: Determination of region-specific pyrazole ring formation by NOESY. Bioorganic and Medicinal Chemistry Letters, 26(12), 2893-2899.
• 13. Abdellatif, K.R., Elsaady, M.T., Abdel-Aziz, S.A., Abusabaa, A.H. (2016). Synthesis, cyclooxygenase inhibition and antiinflammatory evaluation of new 1,3,5-triaryl-4,5-dihydro-1H-pyrazole derivatives possessing methanesulphonyl pharmacophore. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(6), 1545-1555.
• 14. Gedawy, E.M., Kassab, A.E., El Kerdawy, A.M. (2020). Design, synthesis and biological evaluation of novel pyrazole sulfonamide derivatives as dual COX2/5-LOX inhibitors. European Journal of Medicinal Chemistry, 189, 112066.
• 15. Akhtar, W., Marella, A., Alam, M.M., Khan, M.F., Akhtar, M., Anwer, T., Khan, F., Naematullah M., Azam, F., Rizvi, M.A., Shaquiquzzaman, M.(2021). Design and synthesis of pyrazole–pyrazoline hybrids as cancer‐associated selective COX‐2 inhibitors. Archive der Pharmazie, 354, e2000116.
• 16. Costa, R.F., Turones, L.C., Cavalcante, K.V.N., Rosa Júnior, I.A., Xavier, C.H., Rosseto, L.P., Napolitano, H.B., Castro, P.F.D.S., Neto, M.L.F., Galvão, G.M., Menegatti, R., Pedrino, G.R., Costa, E.A., Martins, J.L.R., Fajemiroye, J.O. (2021). Heterocyclic compounds: pharmacology of pyrazole analogs from rational structural considerations. Frontiers in Pharmacology, 12, 666725.
• 17. Protein Data Bank(PDB) https://www.rcsb.org/
• 18. Flamandita, D., Sahlan, M., Lischer, K., Pratami, D.K. (2019). Molecular docking study of antiinflammatory biomarkers in sulawesi propolis as potent inhibitors of cyclooxygenase-2. in 2nd IEEE International Conference on Innovative Research and Development, ICIRD 2019., 9074773, Institute of Electrical and Electronics Engineers Inc., Depok, Indonesia, 28/06/19. https://doi.org/10.1109/ICIRD47319.2019.9074773
• 19. AutoDockTools, the free GUI for AutoDock. [http://autodock.scripps.edu/resources/adt].
• 20. Hanwell, M.D., Curtis, D.E., Lonie, D.C., Vandermeersch, T., Zurek, E., Hutchison, G.R. (2012). "Avogadro: An advanced semantic chemical editor, visualisation, and analysis platform". Journal of Cheminformatics, 4, 17.
• 21. Trott, O., Olson, A.J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimisation and multithreading. Journal of Computational Chemistry, 31, 455-461.
• 22. Barnum, D., Greene, J., Smellie, A. and Sprague, P. (1996) Identification of common functional configurations among molecules. Journal of Chemical Information and Computer Sciences 36, 563–571.