Treating Alzheimer’s Disease through the Circadian Rhythm: Advancements in Drug Discovery and Computer Simulations

Abstract This review explores the intricate link between circadian rhythm dysfunction and Alzheimer’s disease (AD), highlighting the growing importance of this link as a source of novel therapeutic targets for AD treatment. Circadian rhythms, fundamental 24 h biological cycles, are disrupted in AD, with alterations often preceding clinical symptoms and contributing to key pathological hallmarks like beta-amyloid accumulation, Tau hyperphosphorylation, neuroinflammation, and oxidative stress. Due to the multifactorial and complex nature of AD, pharmacological interventions aimed at acting on multiple pathogenic pathways simultaneously present a promising strategy to slow AD progression. In silico methods and computer simulations have advanced drug development and aided the exploration of targets at the interface between AD and circadian rhythms by offering cost-effective and time-efficient ways to elucidate new drug targets and identify potential drug candidates. Computational methods have been successfully applied to identify modulators for core clock components like CLOCK/BMAL1 and CRY1/2, kinases such as glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinase 5 (CDK5), and sleep−wake cycle regulators, including melatonin and orexin receptors. Furthermore, advanced artificial intelligence (AI) frameworks, such as AlphaFold2/3, are revolutionizing structure prediction and accelerating the exploration of vast chemical spaces for potent ligands. The review also emphasizes the need for best practices in validation and transparent reporting to ensure the reproducibility and credibility of these rapidly evolving computational advancements in drug discovery while highlighting the translational gap that still separates the computational hits from clinical application.