Multitargeted drug strategies for Alzheimer's and Parkinson's diseases

Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are multifactorial diseases that are characterized by several interconnected pathological mechanisms, such as the aggregation of amyloid-beta (Aβ), hyperphosphorylation of tau, accumulation of α-synuclein, oxidative stress, mitochondrial dysfunction, neuroinflammation, and neurotransmitter imbalance. Conventional single-target therapies failed to produce significant clinical effects due to the fact that they target only individual disease pathways. Thus, the multitarget-directed ligand (MTDL) strategy has become an attractive therapeutic option, and MTDLs can act on several pathological targets simultaneously. Recent advances in multitarget drug development for AD and PD targeting compounds targeting Aβ, BACE1, MAO-B, cholinesterases, metal-ion dyshomeostasis, oxidative stress, and inflammatory pathways are reviewed. A few potential candidates, such as GV-971, Prasinezumab, Huperzine A, curcumin derivatives, and hybrids of MAO-B inhibitors, have shown neuroprotective and cognitive effects in preclinical and clinical studies. There are significant advances in the clinical pipeline, with over 180 clinical trials for AD and over 130 clinical trials for PD testing multitarget or disease-modifying strategies. The review also highlights the growing importance of computer-aided drug design (CADD), artificial intelligence (AI), and machine learning (ML) in speeding up the discovery of MTDL, optimizing their pharmacokinetic profiles, and predicting multitarget interactions. However, there are still major obstacles to be overcome, such as the ability to cross the blood-brain barrier, optimizing the pharmacokinetics, the difficulties of transferring from the animal to the human model, and the complexity of the regulatory process. New strategies based on nanomedicine, biomarker-driven trials, personalized medicine, and drug repurposing will enhance therapeutic precision and clinical success.