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CNS & Neurological Disorders - Drug Targets

Author(s): F. Sezer Senol Deniz, Ramin Ekhteiari Salmas, Esra Emerce, Bilge Sener and Ilkay Erdogan Orhan*

DOI: 10.2174/1871527322666230417083053

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Cholinesterase Inhibitory and In Silico Toxicity Assessment of Thirty-Four Isoquinoline Alkaloids - Berberine as the Lead Compound

Page: [773 - 783] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Cholinesterase (ChE) inhibitors used currently in clinics for the treatment of Alzheimer’s disease (AD) are the most prescribed drug class with nitrogen-containing chemical formula. Galanthamine, the latest generation anti-ChE drug, contains an isoquinoline structure.

Objective: The aim of the current study was to investigate the inhibitory potential of thirty-four isoquinoline alkaloids, e.g. (-)-adlumidine, β-allocryptopine, berberine, (+)-bicuculline, (-)-bicuculline, (+)-bulbocapnine, (-)-canadine, (±)-chelidimerine, corydaldine, (±)-corydalidzine, (-)-corydalmine, (+)-cularicine, dehydrocavidine, (+)-fumariline, (-)-fumarophycine, (+)-α-hydrastine, (+)-isoboldine, 13-methylcolumbamine, (-)-norjuziphine, norsanguinarine, (-)-ophiocarpine, (-)-ophiocarpine-Noxide, oxocularine, oxosarcocapnine, palmatine, (+)-parfumine, protopine, (+)-reticuline, sanguinarine, (+)-scoulerine, (±)-sibiricine, (±)-sibiricine acetate, (-)-sinactine, and (-)-stylopine isolated from several Fumaria (fumitory) and Corydalis species towards acetyl- (AChE) and butyrylcholinesterase (BChE) by microtiter plate assays. The alkaloids with strong ChE inhibition were proceeded to molecular docking simulations as well as in silico toxicity screening for their mutagenic capacity through VEGA QSAR (AMES test) consensus model and VEGA platform as statistical approaches. The inputs were evaluated in a simplified molecular input-line entry system (SMILES).

Methods: ChE inhibition assays indicated that the highest AChE inhibition was caused by berberine (IC50: 0.72 ± 0.04 μg/mL), palmatine (IC50: 6.29 ± 0.61 μg/mL), β-allocryptopine (IC50: 10.62 ± 0.45 μg/mL), (-)-sinactine (IC50: 11.94 ± 0.44 μg/mL), and dehydrocavidine (IC50: 15.01 ± 1.87 μg/mL) as compared to that of galanthamine (IC50: 0.74 ± 0.01 μg/mL), the reference drug with isoquinoline skeleton. Less number of the tested alkaloids exhibited notable BChE inhibition. Among them, berberine (IC50: 7.67 ± 0.36 μg/mL) and (-)-corydalmine (IC50: 7.78 ± 0.38 μg/mL) displayed a stronger inhibition than that of galanthamine (IC50: 12.02 ± 0.25 μg/mL). The mutagenic activity was shown for β-allocryptopine, (+)- and (-)-bicuculline, (±)-corydalidzine, (-)-corydalmine, (+)-cularicine, (-)- fumarophycine, (-)-norjuziphine, (-)-ophiocarpine-N-oxide, (+)-scoulerine, (-)-sinactine, and (-)- stylopine by means of in silico experiments.

Results: The results obtained by molecular docking simulations of berberine, palmatine, and (-)- corydalmine suggested that the estimated free ligand-binding energies of these compounds inside the binding domains of their targets are reasonable to make them capable of establishing strong polar and nonpolar bonds with the atoms of the active site amino acids.

Conclusion: Our findings revealed that berberine, palmatin, and (-)-corydalmine stand out as the most promising isoquinoline alkaloids in terms of ChE inhibition. Among them, berberine has displayed a robust dual inhibition against both ChEs and could be evaluated further as a lead compound for AD.

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