RESEARCH ARTICLE


Asenapine as a Potential Lead Inhibitor against Central Ca2+/Calmodulin-Dependent Protein Kinase II: Investigation by Docking Simulation and Experimental Validation



Safa Daoud1, *, Reem Abutayeh1, Shada J. Alabed2, Mutasem O. Taha3
1 Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Applied Science Private University, Amman, Jordan
2 Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
3 Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman, Jordan


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Creative Commons License
© 2023 Daoud et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Applied Science Private University, Amman, Jordan; Tel: 00962-65609999; Ext: 1352; E-mail: s_daoud@asu.edu.jo


Abstract

Aim:

The aim of this potential repurposing study is to investigate the potential inhibitory activity of asenapine against central nervous system CaMKII isozymes using docking experiments and enzymatic assay.

Background:

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional protein kinase ubiquitously expressed throughout the brain. Emerging biological data have indicated that inhibiting central nervous system CaMKII isoforms, namely, CaMKIIα and CaMKIIβ, may be a promising therapeutic strategy for the potential treatment of many neurological diseases including schizophrenia, depression, epilepsy, and learning deficit.

Objective:

1- Study the possible attractive interactions of asenapine within the binding sites of the central CaMKII isozymes. 2- Evaluate the inhibitory activities of asenapine against central CaMKII isozymes.

Methods:

Docking experiments of asenapine and other known CaMKII inhibitors were performed. Docking settings were validated using ROC analysis. After that, the inhibitory activities of asenapine against central CaMKII alpha and beta were evaluated by enzymatic assay.

Result:

Docking and scoring experiments of asenapine showed several binding interactions anchoring asenapine within CaMKIIα and CaMKIIβ catalytic sites while enzymatic assay results revealed that asenapine can inhibit CaMKIIα and CaMKIIβ in the micromolar range.

Conclusion:

Our study provides evidence that asenapine can serve as a promising lead for the development of new CaMKIIα and CaMKIIβ inhibitors. Moreover, this study reinforces how the investment in drug repurposing could boost the drug discovery process.

Keywords: CaMKII, Asenapine, Neurological diseases, Docking, Drug repurposing, Lead.