GSK-3β inhibitörleri için in siliko ilaç yeniden konumlandırma

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 (e.g., Alzheimer's disease) and are collectively referred to as "tauopathies". The most notable kinase identified in tau phosphorylation is glycogen synthase kinase 3 (GSK3). 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 (e.g., HIT 2.0, PubChem, and ChEMBL) were searched for potential inhibitory drugs against GSK-3β and found 58 drugs. 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 (PDB ID: 5K5N) 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 (PDB ID: 6QH), a highly selective brain-penetrant kinase inhibitor]. Nabumetone is an NSAID used to treat some arthritis, postoperative pains, and dysmenorrhea. Our results suggest that nabumetone may be a potential inhibitor of GSK-3β.