The promising impact of Bemcentinib and Repotrectinib on sleep impairment in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD), the most prevalent neurodegenerative disease, demands effective medication to alleviate symptoms. This study focused on sleep impairment as an overt clinical symptom and tauopathy as a prominent molecular symptom of this disease. Multiple compounds from three biomolecule libraries (719 compounds; ChemDiv:366 – ChEMBL:180 – PubChem:173) were evaluated for potential binding affinity and safety using AutoDock Vina and pkCSM, respectively, resulting in the selection of four candidate compounds (Lestaurtinib, Repotrectinib, Bemcentinib, and Zotiraciclib). Due to the similarity of Repotrectinib and Bemcentinib binding sites to ATP, 300 ns Martini 3 coarse-grained molecular dynamics (MD) was performed on these two molecules and ATP by NAMD. The stability of tau protein in the presence of drugs was assessed using a 200 ns Martini 3 MD simulation. Binding site analysis discloses Bemcentinib and Repotrectinib as two inhibitors occupying most amino acids in binding with ATP. The RMSD and RMS average correlation results revealed protein containing Bemcentinib and Repotrectinib to have a more stable state compared to ATP in the first 220 ns simulation. There was only a single detachment of Bemcentinib, while Repotrictinib detached twice at the end of the simulation. Eventually, adding Bemcentinib and Repotrectinib to the enzyme-tau complex significantly increased the number of tau detachments during the 200 ns simulation. We report Bemcentinib and Repotrectinib, formerly prescribed for cancer, as potential inhibitors of the CK1 δ. Besides their high binding affinity compared to ATP, they can inhibit all ATP-binding sites and alter the tau binding stability.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alzheimer’s disease
• tauopathy
• molecular dynamics
• CK1δ
• insomnia

Acknowledgments

The authors are grateful to the research vice-chancellor of the Iran University of Medical Sciences (IUMS), Tehran, Iran. All methods and analyses were performed according to Ethics Committee instructions (IUMS Alzheimer′s clinical research section)

Author contribution

Armin Ariaei contributes to study design, writing, and data analysis. Fatemeh Ramazani contributed to the data analysis.

Data availability statement

The data that support the findings of this study are available upon reasonable request from the corresponding author.

Disclosure statement

The authors have no relevant financial or non-financial interests to disclose

Geolocation information

This work is classified in the area of drug discovery via in silico methods which consist of molecular dynamics and molecular interaction.

Additional information

Funding

There was no external funding source for this project. All of the costs were paid by the corresponding author.