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

GSK-3β inhibitörleri için in siliko ilaç yeniden konumlandırma

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

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