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

Curr Alzheimer Res. 2024;20(12):862-874. doi: 10.2174/0115672050301014240315065235.

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.

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

MeSH terms

  • ARNTL Transcription Factors* / genetics
  • ARNTL Transcription Factors* / metabolism
  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • CLOCK Proteins* / genetics
  • CLOCK Proteins* / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use
  • Humans
  • Melatonin* / pharmacology
  • Melatonin* / therapeutic use
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation

Substances

  • ARNTL Transcription Factors
  • Melatonin
  • CLOCK Proteins
  • BMAL1 protein, human
  • Cholinesterase Inhibitors