MS HASTALIĞININ TEDAVİSİNE YÖNELİK YENİ SFİNGOSİN-1-FOSFAT RESEPTÖR MODÜLATÖRLERİNİN GELİŞTİRİLMESİ

Year 2022, , 102 - 114, 01.03.2022

Birsen Huylu , Gozde Yalcin

https://doi.org/10.36306/konjes.1000363

Cited By: 2

Abstract

Hesaplamalı ilaç tasarımı; ilaç geliştirme prosesini hızlandırmakla birlikte maliyeti de düşürerek tıp mühendisliğinin önde gelen alanlarından birine dönüşmüştür. MS hastalığı ölümle sonuçlanmasının yanı sıra, hastalarda yaşam kalitesini düşürmesi nedeniyle de ilaç geliştirme çalışmaları için büyük bir hedef olmayı sürdürmektedir. Sfingosin-1-fosfat reseptörü 1 (S1P1) bir G protein kapılı reseptördür ve MS hastalığının semptomlarının ekspresyonuna ve ilerlemesine yol açan önemli bir mekanizmada etkindir. Bu durum S1P1’i ilaç geliştirme çalışmaları için önemli bir hedef haline getirmektedir. Literatürde S1P1 modülasyonu hakkında ön klinik ve klinik çalışmalar tespit edilmiş olmasına rağmen seçiciliği yüksek modülatörlere rastlanmamıştır. Çalışmamız kapsamında BindingDB veri tabanı vasıtasıyla ulaşılan S1P1 modülatörlerine PharmaGist Web sunucusu vasıtasıyla farmakofor modelleme çalışmasına uygulanmıştır. Bu yöntem ligandların esnek bir biçimde üst üste çakıştırılması prosesi temeline dayanmaktadır. Ardından Autodock Vina programıyla moleküler kenetleme işlemi gerçekleştirilmiş, sonuçlar literatürdeki S1P1 antagonisti ile kıyaslanmıştır. PharmaGist'den alınan en iyi farmakofor modellerine göre ZINCPharmer veri tabanı üzerinden 80 molekül elde edilmiş bu moleküllere in siliko ADME/Toksikoloji işlemi uygulanmıştır. ADME/toksikoloji incelemesi ile elde edilen 4 molekül ZINC00390492, ZINC67740009, ZINC19847253 ve ZINC19847241’dir. Bütün moleküllerin bağlanma profili literatüre ve ML5 antagonistine benzer olarak belirlenmiştir ancak özellikle ZINC00390492 molekülünün bağlanma afinitesi (-8.6 kcal/mol) ML5 antagonistinin bağlanma afinitesinden (-8.4 kcal/mol) düşük bulunmuştur. Sonuç olarak bu çalışma ile ZINC00390492 molekülünün MS Hastalığının tedavisi için önder bir bileşik olabileceği hesaplamalı çalışmalar ile ortaya konulmuştur.

Keywords

Farmakofor Modelleme, Hesaplamalı İlaç Tasarımı, MS Hastalığı, Moleküler kenetleme, Sfingozin-1-fosfat reseptörü 1 (S1P1)

Development of New Sphingosine-1-Phosphate Receptor Modulators for the Treatment of MS Disease

Abstract

Computational drug design; has turned into one of the leading fields of medical engineering by speeding up the drug development process and reducing the cost. MS Disease continues to be a major target for drug development studies, as it results in death and reduces the quality of life in patients. Sphingosine-1-phosphate receptor 1 (S1P1) is a G protein-coupled receptor and is active in an important mechanism that leads to the expression and progression of the symptoms of MS. This makes S1P1 an important target for drug development studies. Although preclinical and clinical studies on S1P1 modulation have been identified in the literature, modulators with high selectivity have not been found. Within the scope of our study, pharmacophore modeling was applied via the PharmaGist Web server to S1P1 modulators accessed through the BindingDB database. This method is based on the process of flexible superposition of ligands. Then, molecular docking was performed with the Autodock Vina program, and the results were compared with the S1P1 antagonist in the literature. According to the best pharmacophore models of PharmaGist, 80 molecules were obtained from the ZINCPharmer database, and in silico, ADME/Toxicology was implemented to these molecules. The 4 molecules obtained by ADME/toxicology examination are ZINC00390492, ZINC67740009, ZINC19847253, and ZINC19847241. The binding profiles of all molecules were determined to be similar to the literature and the ML5 antagonist, but the binding affinity (-8.6 kcal/mol) of the ZINC00390492 molecule was found to be less than the binding affinity of the ML5 antagonist (-8.4 kcal/mol). As a result, with this study, it has been demonstrated by computational studies that the ZINC00390492 molecule can be a promising therapeutic agent for the treatment of MS Disease.

Keywords

Pharmacophore Modeling, Computational Drug Design, MS Disease, Molecular Docking, Sphingosine-1-phosphate receptor 1 (S1P1)

References

• Brandstadter, R., Katz Sand, I., 2017, “The use of natalizumab for multiple sclerosis”, Neuropsychiatr. Dis. Treat., Cilt 13, ss. 1691–1702. doi:10.2147/NDT.S114636.
• Brinkmann, V., 2007, “Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology”, Pharmacol. Ther., Cilt 115, ss. 84–105.
• Calabresi, P. A., Radue, E. W., Goodin, D., et al., 2014, “Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial”, Lancet Neurol., Cilt 13, Sayı 6, ss. 545–56.
• Chen, X., Liu, M., Gilson, M. K., 2001, “BindingDB: A Web-Accessible Molecular Recognition Database”, Combinatorial Chemistry & High Throughput Screening, Cilt 4, Sayı 8, ss. 719–25.
• Daina, A., Olivier, M., Vincent, Z., 2017, “SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules”, Scientific Reports, Cilt 7, ss. 1–13.
• Dassault Systèmes. 2019. “Discovery Studio Visualizer.”
• 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, Cilt 49, Sayı 10, ss. 2333–43.
• Friese, M. A., Schattling, B., Fugger, L., 2014, “Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis”, Nature Reviews Neurology, Nature Publishing Group.
• Hanson, M. A., Roth, C. B., Jo, E., Griffith, M. T., Scott, F. L., Reinhart, G., et al., 2012, “Crystal structure of a lipid G protein-coupled receptor”, Science, Cilt 335, Sayı 6070, ss. 851–855.
• Hauser, S. L., Bar-Or, A., Comi, G., Giovannoni, G., Hartung, H.-P.; Hemmer, B., Lublin, F., Montalban, X., Rammohan, K. W., Selmaj, K., Traboulsee, A., Wolinsky, J. S., Arnold, D. L., Klingelschmitt, G., Masterman, D., Fontoura, P., Belachew, S., Chin, P., Mairon, N., Garren, H. & Kappos, L., 2017, “Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis”, New England Journal of Medicine, Cilt 376, Sayı 3, ss. 221-234.
• Hauser, S. L., Cree, B. A. C., 2020, “Treatment of Multiple Sclerosis: A Review”, American Journal of Medicine. Elsevier Inc.
• Kappos, L., Bar-Or A., Cree, B. A. C., et al., 2018, “Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study”, Lancet, Cilt 391, Sayı 10127, ss. 1263–73.
• Koes, D. R., and Camacho, C. J., 2012, “ZINCPharmer: Pharmacophore Search of the ZINC Database.” Nucleic Acids Research, Cilt 40, ss. 409–14.
• Lee, M. J., Van Brockly, J. R., Thangada, S., Liu, C. H., Hand, A. R., Menzeleev, R., et al., 1998, “Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1”, Science, Cilt 279, ss. 1552–1555.
• Marciniak, A., Camp, S.M., Garcia, J.G.N., Polt, R., 2020, “In silico Docking Studies of Fingolimod and S1P1 Agonists”, Front. Pharmacol., Cilt 11, Sayı 247.
• Massacesi, L., Genain, C.P., Lee-Parritz D., Letvin N.L., Canfield D., Hauser S.L., 1995, “Active and passively induced experimental autoimmune encephalomyelitis in common marmosets: a new model for multiple sclerosis”, Ann. Neurol., Cilt 37, Sayı 4, ss. 519–30.
• Matthews, P. M., 2019, “Chronic inflammation in multiple sclerosis — seeing what was always there.” Nat. Rev. Neurol., Cilt 15, ss. 582–593. doi:10.1038/s41582-019-0240-y.
• Morris, G. M., Ruth, H., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., and Olson, A. J., 2009, “AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility.” Journal of Computational Chemistry, Cilt 30, Sayı 16, ss. 2785–91.
• Moser, T., Akgün, K., Proschmann, U., Sellner, J., and Ziemssen, T., 2020, “The role of TH17 cells in multiple sclerosis: Therapeutic implications.” Autoimmun. Rev., Cilt 19, ss. 102647. doi:https://doi.org/10.1016/j.autrev.2020.102647.
• Murphy, M. P., 2009, “How mitochondria produce reactive oxygen species”, Biochemical Journal. Rudick, R.A., Stuart, W.H., Calabresi, P.A., et al., 2006, “Natalizumab plus interferon beta-1a for relapsing multiple sclerosis”, N. Engl. J. Med., Cilt 354, Sayı 9, ss. 911–23.
• Toman, R. E., Spiegel, S., 2002, “Lysophospholipid receptors in the nervous system”, Neurochem. Res., Cilt 27, ss. 619–627.
• 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, Cilt 31, Sayı 2, ss. 455–61.
• Wan, E. C. K., 2020, “Cellular and Molecular Mechanisms in the Pathogenesis of Multiple Sclerosis”, Cells, Cilt 9, Sayı 10, 2223.