Interaction of the hybrid molecule ADK-1113 with σ₁-, NMDA-, and AMPA-receptors: a molecular docking and molecular dynamics study

Background. Parkinson’s disease has a multifactorial pathogenesis involving glutamate excitotoxicity, oxidative stress, neuroinflammation, and dysregulation of neurotransmitter systems. Therefore, the development of multitarget compounds capable of interacting with several pathogenetically relevant targets is a promising research direction.

Objective. Evaluation of the interaction of the hybrid molecule ADK-1113, designed on the basis of structural fragments of fabomotizole and memantine, with σ₁, NMDA, and AMPA receptors using molecular modeling methods.

Methods. Molecular docking of ADK-1113 was performed using the structures of σ₁-, NMDA-, and AMPA-receptors, followed by molecular dynamics (MD) simulations of the resulting complexes. Binding stability was assessed based on ligand retention within the binding site, root mean square deviation (RMSD) values, the pattern of noncovalent interactions, and binding free energy calculated using the MM/PBSA method (Molecular Mechanics/Poisson–Boltzmann Surface Area).

Results. ADK-1113 bound to all studied receptors and remained within their binding sites during molecular dynamics simulations. The most stable complex was observed for the σ₁-receptor, which was consistent with the most negative binding free energy values obtained by MM/PBSA. The complex with the NMDA-receptor showed intermediate stability, whereas the least favorable binding energy values were obtained for the AMPA-receptor.

Conclusion. The obtained data indicate the potential multitarget activity of ADK-1113 and its ability to interact with several components of neurotransmitter systems. The results of in silico modeling require further experimental confirmation.

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