ABSTRACT
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Although the cause and pathophysiology of the disease are unknown, acetylcholinesterase (AChE) has been identified as a potential therapeutic target. Compounds from the Drug Bank and ZINC subset drug-like databases were screened using ligand-based pharmacophore filtering and molecular docking in this study. Other potential therapeutic targets under investigation include glycogen synthase kinase 3 (GSK-3), beta-secretase (BACE-1), and others. The combined analysis identified 139 potentially active and multi-target ligands targeting two or more enzymes, including c-Jun N-terminal kinase 3 (JNK-3), protein tyrosine phosphatase 1B (PTP1B), and nicotinamide adenine dinucleotide phosphate oxidase. ZINC-27 and ZINC-1–4, which inhibit AChE, GSK-3, and BACE-1, were discovered utilizing a combination of compound profiling, ADMET prediction, and structural modification. In conclusion, the multi-approach study revealed that ZINC-27 and ZINC-1–4 have the potential to be multi-target anti-AD drugs that simultaneously target AChE, GSK-3, and BACE-1, and thus warrant further investigation.
