MS HASTALIĞININ TEDAVİSİ İÇİN YENİ SİKLOFİLİN D RESEPTÖR İNHİBİTÖRLERİNİN GELİŞTİRİLMESİ

Öz

Amaç: Bu çalışmada, multipl skleroz (MS) hastalığında mitokondriyal fonksiyon bozukluğuna neden olan siklofilin D (CypD) reseptörünün inhibisyonu için yeni moleküllerin geliştirilmesine yönelik hesaplamalı çalışmaların yapılması amaçlanmıştır.

Gereç ve Yöntem: Literatür taraması ile tespit edilen CypD inhibitörlerine PharmaGist Web sunucusu üzerinden farmakofor modelleme çalışması uygulanmıştır. PharmaGist'in en iyi farmakofor modellerine göre ZINCPharmer veri tabanından 80 molekül elde edilmiş ve bu moleküllere in silico ADME/Toksikoloji analizi uygulanmıştır. Daha sonra Autodock Vina programı ile ADME/Tox analizleri sonucunda en iyi sonucu veren ligandlar ile moleküler yerleştirme yapılmıştır.

Sonuç ve Tartışma: ZINC00390492 molekülü hem CypD, hem de Sfingosin-1-fosfat reseptörü 1 ile en iyi bağlanma afinitesi ve bağlanma profilini göstermektedir. Bu molekülün, MS tedavisi için bir öncü molekül olabileceği gösterilmiştir.

Anahtar Kelimeler

• Farmakofor modelleme
• in silico
• moleküler doking
• multipl skleroz
• siklofilin D

DEVELOPMENT OF NEW CYCLOPHILIN D RECEPTOR INHIBITORS FOR THE TREATMENT OF MULTIPLE SCLEROSIS

Öz

Objective: In this study, it was aimed to carry out computational studies for the development of new molecules for the inhibition of the cyclophilin D (CypD) receptor, which causes the disability of mitochondrial function in multiple sclerosis (MS) disease.

Material and Method: Pharmacophore modeling study was applied via the PharmaGist Web server to the CypD inhibitors detected by the literature search. According to the best pharmacophore models from PharmaGist, 80 molecules were obtained from the ZINCPharmer database, and in silico ADME/Toxicology analysis was applied to these molecules. Then, molecular docking was performed with the ligands that gave the best results as a result of ADME/Tox analyses with the Autodock Vina program.

Result and Discussion: ZINC00390492 molecule shows the best binding affinity and binding profile with both CypD, Sphingosine-1-phosphate receptor 1. It has been demonstrated that this molecule may be a lead molecule for the treatment of MS. 

Anahtar Kelimeler

• Cyclophilin D
• in silico
• Molecular docking
• Multiple Sclerosis
• Pharmacophore modeling

Kaynakça

1. Alavian, K. N., Beutner, G., Lazrove, E., Sacchetti, S., Park, H. A., Licznerski, P., Li, H., Nabili, P., Hockensmith, K., Graham, M., Porter, G. A., Jonas, E. A. (2014). An uncoupling channel within the c-subunit ring of the F1F O ATP synthase is the mitochondrial permeability transition pore. Proceedings of the National Academy of Sciences of the United States of America, 111(29), 10580–10585. [CrossRef]
2. Azzolin, L., Antolini, N., Calderan, A., Ruzza, P., Sciacovelli, M., Marin, O., Mammi, S., Bernardi, P., Rasola, A. (2011). Antamanide, a derivative of amanita phalloides, is a novel inhibitor of the mitochondrial permeability transition pore. PLoS ONE, 6(1), 26–29. [CrossRef]
3. Baines, C. P., Kaiser, R. A., Purcell, N. H., Blair, N. S., Osinska, H., Hambleton, M. A., Brunskill, E. W., Sayen, M. R., Gottlieb, R. A., Dorn II, G. W., Molkentin, J. R. (2004). Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature, 430(7003), 984–984. [CrossRef]
4. Basso, E., Fante, L., Fowlkes, J., Petronilli, V., Forte, M. A., Bernardi, P. (2005). Properties of the permeability transition pore in mitochondria devoid of cyclophilin D. Journal of Biological Chemistry, 280(19), 18558–18561. [CrossRef]
5. Basso, E., Petronilli, V., Forte, M. A., Bernardi, P. (2008). Phosphate is essential for inhibition of the mitochondrial permeability transition pore by cyclosporin A and by cyclophilin D ablation. Journal of Biological Chemistry, 283(39), 26307–26311. [CrossRef]
6. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N., Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Research, 28(1), 235–242. [CrossRef]
7. Clarke, S. J., McStay, G. P., Halestrap, A. P. (2002). Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A. Journal of Biological Chemistry, 277(38), 34793–34799. [CrossRef]
8. Daina, A., Michielin, O., Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(October 2016), 1–13. [CrossRef]

9. Damsker, J. M., Bukrinsky, M. I., Constant, S. L. (2007). Preferential chemotaxis of activated human CD4 + T cells by extracellular cyclophilin A . Journal of Leukocyte Biology, 82(3), 613–618. [CrossRef]
10. Dassault Systèmes. (2019). Discovery Studio Visualizer (No. 2019). BIOVIA. [CrossRef]
11. Dror, O., Schneidman-Duhovny, D., Inbar, Y., Nussinov, R., Wolfson, H. J. (2009). Novel approach for efficient pharmacophore-based virtual screening: Method and applications. Journal of Chemical Information and Modeling, 49(10), 2333–2343. [CrossRef]
12. Forte, M., Gold, B. G., Marracci, G., Chaudhary, P., Basso, E., Johnsen, D., Yu, X., Fowlkes, J., Bernardi, P., Bourdette, D. (2007). Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 104(18), 7558–7563. [CrossRef]
13. Frohman, E. M., Racke, M. K., & Raine, C. S. (2006). Multiple Sclerosis — The Plaque and Its Pathogenesis. New England Journal of Medicine, 354(9), 942–955. [CrossRef]
14. Galat, A. (2004). Function-dependent clustering of orthologues and paralogues of cyclophilins. In Proteins: Structure, Function and Genetics (Vol. 56, Issue 4, pp. 808–820). [CrossRef]
15. Galat, A., Metcalfe, S. M. (1995). Peptidylproline cis/trans isomerases. Progress in Biophysics and Molecular Biology, 63(1), 67–118. [CrossRef]
16. Huylu, B., Yalcin Ozkat, G. (2022). MS Hastalığının Tedavi̇si̇ne Yöneli̇k Yeni Sfi̇ngosi̇n-1-Fosfat Reseptör Modülatörleri̇nin Geli̇şti̇ri̇lmesi̇. Konya Journal of Engineering Sciences, 10(1), 102–114. [CrossRef]
17. Ivery, M. T. G. (2000). Immunophilins: Switched on protein binding domains? In Medicinal Research Reviews (Vol. 20, Issue 6, pp. 452–484). [CrossRef]
18. Koes, D. R., Camacho, C. J. (2012). ZINCPharmer: Pharmacophore search of the ZINC database. Nucleic Acids Research, 40(W1), 409–414. [CrossRef]
19. Kong, W., Li, S., Longaker, M. T., Lorenz, H. P. (2007). Cyclophilin C-associated protein is up-regulated during wound healing. In Journal of Cellular Physiology (Vol. 210, Issue 1, pp. 153–160). [CrossRef]
20. Lee, J., Kim, S. S. (2010). An overview of cyclophilins in human cancers. Journal of International Medical Research, 38(5), 1561–1574. [CrossRef]
21. Lin, K., Gallay, P. (2013). Curing a viral infection by targeting the host: The example of cyclophilin inhibitors. Antiviral Research, 99(1), 68–77. [CrossRef]
22. Morris, G. M., Ruth, H., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30(16), 2785–2791. [CrossRef]
23. Murphy, M. P. (2009). How mitochondria produce reactive oxygen species. Biochemical Journal. [CrossRef]
24. Nath, P. R., Dong, G., Braiman, A., Isakov, N. (2014). Immunophilins Control T Lymphocyte Adhesion and Migration by Regulating CrkII Binding to C3G. The Journal of Immunology, 193(8), 3966–3977. [CrossRef]
25. Nicolli, A., Basso, E., Petronilli, V., Wenger, R. M., Bernardi, P. (1996). Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, a cyclosporin A-sensitive channel. Journal of Biological Chemistry, 271(4), 2185–2192. [CrossRef]
26. Ortiz, G. G., Pacheco-Moisés, F. P., Bitzer-Quintero, O. K., Ramírez-Anguiano, A. C., Flores-Alvarado, L. J., Ramírez-Ramírez, V., … Torres-Sánchez, E. D. (2013). Immunology and oxidative stress in multiple sclerosis: Clinical and basic approach. Clinical and Developmental Immunology. [CrossRef]
27. Park, I., Londhe, A. M., Lim, J. W., Park, B. G., Jung, S. Y., Lee, J. Y., Lim, S. M., No, K. T., Lee, J., Pae, A. N. (2017). Discovery of non-peptidic small molecule inhibitors of cyclophilin D as neuroprotective agents in Aβ-induced mitochondrial dysfunction. Journal of Computer-Aided Molecular Design, 31(10), 929–941. [CrossRef]
28. Roydon Price, E., Zydowsky, L. D., Jin, M., Hunter Baker, C., Mckeon, F. D., Walsh, C. T. (1991). Human cyclophilin B: A second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence. Proceedings of the National Academy of Sciences of the United States of America, 88(5), 1903–1907. [CrossRef]
29. Smith, K. J., Lassmann, H. (2002). The role of nitric oxide in multiple sclerosis. Lancet Neurology, 1(4), 232–241. [CrossRef]
30. Spik, G., Haendler, B., Delmas, O., Mariller, C., Chamoux, M., Maes, P., Tartar, A., Montreuil, J., Stedman, K., Kocher, H. P., Keller, R., Hiestand, P. C., Movva, N. R. (1991). A novel secreted cyclophilin-like protein (SCYLP). Journal of Biological Chemistry, 266(17), 10735–10738. [CrossRef]
31. Tanveer, A., Virji, S., Andreeva, L., Totty, N. F., Hsuan, J. J., Ward, J. M., Crompton, M. (1996). Involvement of cyclophilin D in the activation of a mitochondrial pore by Ca2+ and oxidant stress. European Journal of Biochemistry, 238(1), 166–172. [CrossRef]
32. Trott, O., Olson, A. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2), 455–461. [CrossRef]
33. Wolinsky MS Study Group. (1990). Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: A randomized, double‐blinded, placebo‐controlled clinical trial. In Annals of Neurology (Vol. 27, Issue 6, pp. 591–605). [CrossRef]
34. Yurchenko, V., Constant, S., Eisenmesser, E., Bukrinsky, M. (2010). Cyclophilin-CD147 interactions: A new target for anti-inflammatory therapeutics. Clinical and Experimental Immunology, 160(3), 305–317. [CrossRef]