Beyond Conventional Therapies: Molecular Dynamics of Alzheimer's Treatment through CLOCK/BMAL1 Interactions

Ismail Celil Haskologlu; Emine Erdag; Ahmet Ozer Sehirli; Orhan Uludag; Nurettin Abacioglu

doi:10.2174/0115672050301014240315065235

Beyond Conventional Therapies: Molecular Dynamics of Alzheimer's Treatment through CLOCK/BMAL1 Interactions

Curr Alzheimer Res. 2024 Mar 19. doi: 10.2174/0115672050301014240315065235. Online ahead of print.

Authors

Ismail Celil Haskologlu¹, Emine Erdag², Ahmet Ozer Sehirli³, Orhan Uludag⁴, Nurettin Abacioglu¹

Affiliations

¹ Pharmacology Department, Faculty of Pharmacy, Near East University, Nicosia Mersin-10, Near East Boulevard 99138, Türkiye.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Near East University, Nicosia Mersin-10, Near East Boulevard 99138, Türkiye.
³ Pharmacology Department, Faculty of Dentistry, Near East University, Nicosia Mersin-10, Near East Boulevard 99138, Türkiye.
⁴ Clinical Pharmacy Department, Faculty of Pharmacy, Near East University, Nicosia Mersin-10, Near East Boulevard 99138, Türkiye.

PMID: 38509675
DOI: 10.2174/0115672050301014240315065235

Abstract

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. <p> 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. <p> Methods: Using molecular docking and MM/PBSA methodologies, this research determines the binding affinities of drugs within the Bmal1 binding site, constructing interaction profiles. <p> 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. <p> 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.

Keywords: Alzheimer’s disease.; Bmal1; FDA-approved drugs; chronotherapy; melatonin; molecular docking.