Enhancing Quality of Life in Multiple Sclerosis Patients Through Coadministration of FDA-Approved Immunomodulators and Melatonin

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Objective: The primary goal of this study was to assess the binding characteristics and affinities of melatonin and certain U.S. Food and Drug Administration (FDA)-approved lipophilic drugs used in the treatment of multiple sclerosis (MS) with the brain and muscle Arnt-like 1 (BMAL1) clock protein. Additionally, the study aimed to investigate their potential as modulators of BMAL1 activity for therapeutic applications in MS.Methods: Molecular docking and simulation studies were conducted to investigate the interactions between the BMAL1 protein and the selected agents as ligands. Docking simulations were performed using AutoDock Vina, and key interactions were analyzed with Biovia Discovery Studio Visualizer. A molecular dynamics simulation was conducted using GROMACS 2020.4 and the binding free energies were calculated using the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. The pharmacokinetic properties of the ligands were predicted using the BOILED-Egg model implemented in the SwissADME web tool.Results: Melatonin demonstrated the highest binding affinity (-8.5 kcal/mol) and most favorable binding free energy (-245.26±1.27 kJ/mol) with BMAL1, suggesting its potential synergistic activity with other FDA-approved drugs in MS therapy. The pharmacokinetic analysis indicated that all three ligands were likely to cross the blood-brain barrier and exhibit high gastrointestinal absorption, with teriflunomide and melatonin potentially achieving a better profile.Conclusion: This study highlights the potential of concomitant use of melatonin to modulate BMAL1 activity, providing a foundation for developing targeted chronotherapeutic strategies in MS treatment.