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

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.

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.

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.

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.

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.

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.