Title:Beyond Conventional Therapies: Molecular Dynamics of Alzheimer's
Treatment through CLOCK/BMAL1 Interactions
Volume: 20
Issue: 12
Author(s): Ismail Celil Haskologlu*, Emine Erdag, Ahmet Ozer Sehirli, Orhan Uludag and Nurettin Abacioglu
Affiliation:
- Department of Pharmacology, Faculty of Pharmacy, Near East University, Nicosia Mersin-10, Near East Boulevard
99138, Türkiye
Keywords:
Bmal1, molecular docking, FDA-approved drugs, melatonin, chronotherapy, Alzheimer’s disease.
Abstract:
Background: Alzheimer's Disease (AD) represents a neurodegenerative disorder characterized
by cognitive and behavioral impairments significantly hindering social and occupational
functioning. Melatonin, a hormone pivotal in regulating the body's intrinsic circadian rhythm, also
acts as a catalyst in the breakdown of beta-amyloid deposits, offering a promising therapeutic approach
for AD. The upregulation of Brain and Muscle ARNT-Like 1 (Bmal1) gene expression, stimulated
by melatonin, emerges as a potential contributor to AD intervention. Current pharmacological
interventions, such as FDA-approved cholinesterase inhibitors and the recently authorized
monoclonal antibody, Lecanemab, are utilized in AD management. However, the connection between
these medications and Bmal1 remains insufficiently explored.
Objective: This study aims to investigate the molecular effects of FDA-endorsed drugs on the
CLOCK: Bmal1 dimer. Furthermore, considering the interactions between melatonin and Bmal1,
this research explores the potential synergistic efficacy of combining these pharmaceutical agents
with melatonin for AD treatment.
Methods: Using molecular docking and MM/PBSA methodologies, this research determines the
binding affinities of drugs within the Bmal1 binding site, constructing interaction profiles.
Results: The findings reveal that, among FDA-approved drugs, galanthamine and donepezil demonstrate
notably similar binding energy values to melatonin, interacting within the Bmal1 binding
site through analogous amino acid residues and functional groups.
Conclusion: A novel therapeutic approach emerges, suggesting the combination of melatonin
with Lecanemab as a monoclonal antibody therapy. Importantly, prior research has not explored
the effects of FDA-approved drugs on Bmal1 expression or their potential for synergistic effects.
