Virtual screening of phytochemicals against multiple protein targets of Alzheimer’s disease
TL;DR
Several of the identified multitarget phytochemicals are promising candidates for further experimental validation in AD therapy and supported by the literature, which shows that they can inhibit amyloid aggregation, tau phosphorylation, neuroinflammation, and cholinergic dysfunction.
Abstract
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder for which current approved therapies provide temporary symptomatic relief, and no disease-modifying treatments are approved. Given the complex pathology of AD and the growing interest in multitarget therapeutic strategies, we performed structure-based virtual screening to identify phytochemicals capable of modulating multiple AD-related targets. A virtual library of 2,847 phytochemical compounds was docked against ten key proteins implicated in AD identified by literature mining, including: amyloid beta (Aβ), acetylcholinesterase (AChE), apolipoprotein E4 (APOE4), β-secretase (BACE1), butyrylcholinesterase (BChE), brain derived neurotrophic factor (BDNF), cyclin dependent kinase 5 (CDK5), glycogen synthase kinase three beta (GSK3β) and presenilin 1/2 (PSEN1/2). Docking results showed potential strong binding of 96 compounds at multiple key targets, and molecular dynamics simulations of the representative compounds Lactucopicrin, Oleanolic acid and Rutecarpine in complex with AChE and GSK3β demonstrated stable protein-ligand complexes, comparable to the known AChE-ligand, Donepezil, and the GSK3β-ligand, QQA. Post-docking filters based on multitarget and heavy atoms count narrowed the selection to 36 compounds. These 36 compounds were classified into families of Alkaloids (Rutecarpine, Sanguinarine, Strychnine), Steroidal alkaloids (Tomatidine, Cyclopamine, Jervine, Verticine, Verticinone), Steroidal sapogenins (Diosgenin, Hecogenin, Yamogenin, Tigogenin, Smilagenin, Sarsasapogenin, Neogitogenin, Ruscogenin), Triterpenoids/sterols (alpha-Spinasterin, Fucosterol, Stigmasterol, Beta-Sitosterol, gamma-Sitosterol, Isofucosterol, Germanicol, Lupeol, Beta-Amyrin, alpha-Amyrin, Taraxerol, Friedelin, Tetrahymanol, Tingenone, Parkeol, Methylenecycloartanol, Ursolic Acid, Oleanolic Acid, Obacunone), and Sesquiterpene (Lactucopicrin). Multiple compounds were supported by the literature, which shows that they can inhibit amyloid aggregation, tau phosphorylation, neuroinflammation, and cholinergic dysfunction, thus lending credibility to our claims. Collectively, our findings suggest that several of the identified multitarget phytochemicals are promising candidates for further experimental validation in AD therapy.