A Chronobiological Approach: The Potential of Photoswitchable Drug Derivatives in the Treatment of Alzheimer’s Disease

Objective: Alzheimer’s disease (AD) is a progressive neurodegenerative condition significantly affecting cognitive functions, necessitating novel therapeutic approaches. Chronic progression of AD has an involvement of chronopathologic pattern. Traditional treatments primarily involve cholinesterase inhibitors like donepezil, rivastigmine, galantamine, and N-methyl-D-aspartate (NMDA) receptor antagonists such as memantine. These drugs face limitations due to their non-targeted systemic effects and side effects. Therefore, modifying these drugs with a chronobiological treatment approach could be of great importance in treating AD. Methods: In this study, the design of photoswitchable derivatives of these drugs was explored using azobenzene to control drug activity with light, potentially enhancing site-specific action and reducing side effects. The interactions of these derivatives were assessed with target binding sites through molecular docking, molecular dynamics simulations, and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculations. Results: The photoswitchable derivatives demonstrated significantly enhanced binding affinities and stability compared to their traditional counterparts. For instance, photoswitchable derivatives of all tested drug molecules in their planar form showed increased binding energy against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and NMDA receptors. The MM/PBSA results supported these findings, indicating that the photoswitchable derivatives exhibit better stability and efficacy when interacting with their targets. Conclusion: The combination of photoswitchable features with traditional AD drugs could be a promising strategy. This hypothetical approach may not only improve the effectiveness of these drugs but also minimize the risk of negative side effects, opening up new possibilities for managing AD treatment by combining chronobiology and the effects of light.