Identification of Potential Multitarget Directed Ligands for Alzheimer's Disease by Coupling Virtual Screening and...

Area of Science:

• Neuroscience
• Pharmacology
• Computational Chemistry

Background:

• Alzheimer's disease (AD) is a neurodegenerative disorder linked to beta-amyloid plaques, oxidative stress, and reduced cholinergic activity.
• Current Alzheimer's treatments have limitations, highlighting the need for novel therapeutic strategies.
• Multitarget-directed ligands (MTDLs) offer a promising approach by simultaneously addressing multiple AD pathologies.

Purpose of the Study:

• To identify novel MTDLs for Alzheimer's disease (AD) by computationally screening a large compound database against prioritized AD-related protein targets.
• To evaluate the experimental efficacy of identified candidate MTDLs against key enzymes and receptors implicated in AD pathogenesis.
• To investigate the binding interactions of promising compounds using molecular dynamics simulations and assess their safety in cellular models.

Main Methods:

• Prioritized six key Alzheimer's disease (AD) protein targets: acetylcholinesterase (AChE), beta-secretase 1 (BACE-1), cannabinoid receptor type 2 (CB2), glycogen synthase kinase 3 beta (GSK-3β), monoamine oxidase A (MAO-A), and neuronal acetylcholine receptor subunit alpha-7 (nAChR7).
• Employed ligand- and structure-based virtual screening to identify potential MTDLs from a database of 14 million compounds, yielding 21 early-stage candidates.
• Conducted experimental assays for AChE, BACE-1, GSK-3β, MAO-A, nAChR7, BChE, and MAO-B inhibition; performed molecular dynamics simulations and cellular toxicity assessments.

Main Results:

• Virtual screening reduced 14 million compounds to 21 candidates. PJ17 demonstrated dual-target activity with submicromolar inhibition of AChE and GSK-3β.
• PJ11 exhibited significant MAO-B inhibition. Molecular dynamics simulations provided insights into the binding interactions of PJ17 with its targets.
• PJ17 displayed a favorable safety profile in cellular primary cultures, suggesting its potential as a scaffold for AD drug development.

Conclusions:

• The study successfully identified and validated MTDLs for Alzheimer's disease (AD) using a combined computational and experimental approach.
• PJ17 emerged as a promising hit compound with dual inhibitory activity against AChE and GSK-3β and a good safety profile.
• The findings support the use of PJ17 as a template for designing novel multitarget-directed drugs to combat Alzheimer's disease (AD).