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

Year 2022, Volume: 10 Issue: 1, 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)

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