GSK-3β inhibitörleri için in siliko ilaç yeniden konumlandırma

Year 2024, Issue: Special Issue / International Multidisciplinary Symposium on Drug Research and Development, DRD-2023, 11 - 16, 01.07.2024

Elif Deniz , Fuat Karakuş , Burak Kuzu

https://doi.org/10.52794/hujpharm.1361472

Abstract

Mikrotübüllerle ilişkili bir protein olan Tau, merkezi sinir sistemi boyunca yaygın olarak dağılır ve mikrotübüllerin polimerizasyonunu, birleşmesini ve stabilitesini destekler. Tau proteinlerinin hiperfosforilasyonu, çok sayıda nörodejeneratif hastalığın patolojik işareti olan ve toplu olarak "tauopatiler" olarak adlandırılan hücre içi nörofibriler yumaklara yol açar. Tau fosforilasyonunda tanımlanan en dikkate değer kinaz, glikojen sentaz kinaz 3'tür (GSK3). GSK-3 izoformları arasında GSK-3β, nörodejeneratif hastalıkların patofizyolojisi ile ilişkilendirilmiştir. GSK-3β'nın farmakolojik inhibisyonunun bu hastalıklar için potansiyel bir terapötik hedef olduğu öne sürülmüştür. Bu çalışmada GSK-3β'ya karşı potansiyel inhibitör ilaçlar için literatür ve veri tabanları araştırıldı ve 58 ilaç bulundu. İlaçlar, ücretsiz web araçları olan SwissADME, pkCSM ve ProTox-II aracılığıyla fizikokimyasal-farmakolojik özelliklere ve toksisite profillerine göre filtrelendi. Ön filtrelemeden sonra geri kalan yedi ilaçla (Nabumeton, Loxoprofen, Ketoprofen, Oksitetrasiklin, Benzoil Peroksit, Naproksen ve Epinefrin Hidroklorür) GSK-3β'ye karşı moleküler yerleştirme gerçekleştirildi. Sonuçlara göre nabumeton, yedi ilaç arasında GSK-3β'ye karşı en iyi bağlanma enerjisine (-7,39 kcal/mol) ve en düşük konsantrasyonda (3,8 µM) inhibisyon yeteneğine sahipti [PF-04802367 ile karşılaştırıldığında oldukça seçici bir beyin nüfuz edici madde kinaz inhibitörü]. Sonuçlarımız nabumetonun potansiyel bir GSK-3β inhibitörü olabileceğini düşündürmektedir.

Keywords

İlaç yeniden konumlandırma, GSK-3β, in siliko analiz, Nabumeton, tauopatiler

In Silico Drug Repurposing As Inhibitors Against GSK-3β

Abstract

Tau, a protein associated with microtubules, is widely distributed throughout the
central nervous system and promotes the polymerization, assembly, and stability
of microtubules. Hyperphosphorylation of tau proteins leads to intracellular
neurofibrillary tangles, which are the pathological hallmark of numerous neurodegenerative
diseases and are collectively referred to as “tauopathies”. The most
notable kinase identified in tau phosphorylation is glycogen synthase kinase 3
(GSK-3). Among the GSK-3 isoforms, GSK-3β has been linked to the pathophysiology
of neurodegenerative diseases. Pharmacological inhibition of GSK-3β has
been suggested as a potential therapeutic target for these diseases. In this study,
the literature and databases were searched for potential inhibitory drugs against
GSK-3β and 58 drugs were found. The drugs were filtered according to physicochemical-
pharmacological properties and toxicity profiles via SwissADME,
pkCSM, and ProTox-II, free web tools. After pre-filtration, molecular docking
was performed against GSK-3β with the remaining seven drugs (Nabumeton,
Loxoprofen, Ketoprofen, Oxytetracycline, Benzoyl Peroxide, Naproxen, and
Epinephrine Hydrochloride). According to the results, nabumetone had the best
binding energy (-7.39 kcal/mol) and inhibition ability at the lowest concentration
(3.8 μM) against GSK-3β among the seven drugs [compared to PF-04802367, a
highly selective brain-penetrant kinase inhibitor]. Our results suggest that nabumetone
may be a potential inhibitor of GSK-3β.

Keywords

Drug repurposing, GSK-3β, in silico analysis, nabumetone, tauopathies

Ethical Statement

It is declared that ethics committee approval is not required for this study.

Thanks

The authors also thank Van Yüzüncü Yıl University, Faculty of Pharmacy, for the opportunity required for this study.

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