Molecular and Mathematical Models in Parkinson’s and Alzheimer’s Diseases: Optimizing the Timing of Drugs

Circadian rhythms, which regulate various physiological processes, play a significant role in neurodegenerative diseases. This study utilized a detailed mathematical modeling approach to optimize the timing of drug administration for Alzheimer's and Parkinson's medications. The term "optimize the timing of drug administration" refers to the process of determining the most effective dosing schedules based on circadian rhythms. Optimization was defined by aligning drug administration times with the body's natural circadian rhythms to maximize therapeutic efficacy and minimize side effects. Criteria for "optimal dosing schedules" included achieving peak drug concentrations during key periods of circadian protein activity and aligning dosing times with the body’s biological clock. The models integrated pharmacokinetic and pharmacodynamic data with the dynamic interactions of core circadian clock proteins (BMAL۱/CLOCK and PER/CRY) through ordinary differential equations (ODEs). These equations simulated the concentration of these proteins and drugs over time, allowing for the prediction of optimal dosing schedules that align with the body's natural circadian rhythms. The addition of melatonin demonstrated potential benefits. AutoDock Vina and GROMACS software were used for molecular docking simulations. For Alzheimer's disease, simulations identified that Donepezil achieves maximum efficacy when administered at midnight, Memantine in the morning, and Rivastigmine at noon. In Parkinson's disease, Levodopa was most effective when administered in the morning, Pramipexole at noon, and Rasagiline in the evening. Combining these drugs with melatonin resulted in further stabilization of circadian protein levels and extended the therapeutic effects of the drugs. Binding energies for all drug molecules were lower than for melatonin in each clock protein complex, indicating that melatonin could enhance therapy. These findings provide a strong basis for future clinical studies to validate time-optimized pharmacotherapy as a strategy to improve the management of Alzheimer's and Parkinson's diseases.

کلیدواژه ها:

Alzheimer's disease ، Parkinson's disease ، Molecular docking ، Mathematical Modeling ، Melatonin ، circadian rhythm