Targeting multiple pathways with virtual screening to identify the multi-target agent for Alzheimer’s disease treatment

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive memory loss, posing a significant risk, particularly within aging populations. Effective treatments to prevent or cure AD have remained elusive with current treatments only able to slow disease progression. Moreover, challenges in drug development for AD therapies are a complex pathology. A multi-target agent gained considerable interest over the single therapy in complex diseases, providing possible insights into therapeutic development by simultaneously targeting multiple pathological mechanisms. Virtual screening (VS) is a potent computational tool for identifying potential drug candidates from vast chemical databases, with subsequent molecular docking providing detailed insights into ligand-protein interactions. The ZINC database, housing millions of chemical compounds, serves as a valuable resource for screenings. Here, we conducted VS of compounds sourced from the ZINC database to identify potential multi-target AD agents. Through the VS analysis and subsequent in-vitro evaluations, our investigation identified one compound, ZINC006067856 (VS3), as a highly promising hit. This compound exhibited multifaceted actions against key AD pathological features, including cholinesterase inhibition, modulation of amyloid beta (Aβ) aggregation, and promotion of Aβ destabilization. Additionally, VS3 demonstrated neuroprotective effects against hydrogen peroxide-induced cell damage, further highlighting its potential as a comprehensive multi-targeted therapeutic agent for AD. Therefore, our findings suggested that VS3 held promise as a candidate for further preclinical and clinical investigations in the treatment of AD. Further elucidation of its mechanisms of action and comprehensive preclinical evaluations are required to assess its safety, efficacy, and therapeutic potential in improving AD clinical outcomes.