Identification of multi-target directed ligands for Alzheimer’s disease by coupling virtual screening and experimental validation

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with the accumulation of beta-amyloid plaques, oxidative stress, and a decrease in cholinergic activity among other pathologies. Given the limitations of current treatments, multitarget strategies present a promising alternative. This study prioritized six key therapeutic targets associated with AD: 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 the neuronal acetylcholine receptor subunit alpha-7 (nAChR7). Ligand- and structure-based virtual screening methods were applied to identify potential multitarget directed ligands (MTDLs), reducing an initial database of 14 million compounds to 21 candidates that were tested experimentally. From this screening, the compound PJ17 exhibited a multitarget profile with sub-micromolar activity against AChE and GSK-3β. Unbiased molecular dynamics simulations revealed key common interactions between PJ17 and those targets. This offered valuable insights for the further hit-to- lead optimization of this promising MTDL. In addition, PJ17 showed a safe profile in cellular primary culture suggesting its use as a template to design multitarget drugs against AD.