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Structure- and Cation-Dependent Mechanism of Interaction of Tricyclic Antidepressants with NMDA Receptor According to Molecular Modeling Data

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Abstract

Some tricyclic antidepressants (TCAs), including amitriptyline (ATL), clomipramine (CLO), and desipramine (DES), are known to be effective for management of neuropathic pain. It was previously determined that ATL, CLO, and DES are capable of voltage-dependent blocking of NMDA receptors of glutamate (NMDAR), which play a key role in pathogenesis of neuropathic pain. Despite the similar structure of ATL, CLO, and DES, efficacy of their interaction with NMDAR varies significantly. In the study presented here, we applied molecular modeling methods to investigate the mechanism of binding of ATL, CLO, and DES to NMDAR and to identify structural features of the drugs that determine their inhibitory activity against NMDAR. Molecular docking of the studied TCAs into the NMDAR channel was performed. Conformational behavior of the obtained complexes in the lipid bilayer was simulated by the method of molecular dynamics (MD). A single binding site (upper) for the tertiary amines ATL and CLO and two binding sites (upper and lower) for the secondary amine DES were identified inside the NMDAR channel. The upper and lower binding sites are located along the channel axis at different distances from the extracellular side of the plasma membrane. MD simulation revealed that the position of DES in the lower site is stabilized only in the presence of sodium cation inside the NMDAR channel. DES binds more strongly to NMDAR compared to ATL and CLO due to simultaneous interaction of two hydrogen atoms of its cationic group with the asparagine residues of the ion pore of the receptor. This feature may be responsible for the stronger side effects of DES. It has been hypothesized that ATL binds to NMDAR less efficiently compared to DES and CLO due to its lower conformational mobility. The identified features of the structure- and cation-dependent mechanism of interaction between TCAs and NMDAR will help in the further development of effective and safe analgesic therapy.

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Abbreviations

ATL:

amitriptyline

CLO:

clomipramine

DES:

desipramine

ELJ-SR and ECOUL-SR :

the short-range Lennard–Jones and Coulomb energies

MD:

molecular dynamics

MK-801:

dizocilpine

NCX:

sodium-calcium exchanger

NMDAR:

N-methyl-D-aspartate receptor

RMSD:

root mean square deviation of atoms from their initial position

TCAs:

tricyclic antidepressants

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Acknowledgments

The computational experiments were performed in the supercomputer center of the Peter the Great St. Petersburg Polytechnic University (https://scc.spbstu.ru).

Funding

The work was financially supported by the State Reserves of the Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences (no. 075-00264-24-00).

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  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223, St. Petersburg, Russia

    Daria A. Belinskaia & Natalia N. Shestakova

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  1. Daria A. Belinskaia
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D.A.B. planned and performed experiments, discussed the results, and prepared the manuscript; N.N.S. conceptualized and supervised the study, planned and performed experiments, discussed the results, prepared and edited the manuscript.

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Correspondence to Daria A. Belinskaia.

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Belinskaia, D.A., Shestakova, N.N. Structure- and Cation-Dependent Mechanism of Interaction of Tricyclic Antidepressants with NMDA Receptor According to Molecular Modeling Data. Biochemistry Moscow 89, 507–522 (2024). https://doi.org/10.1134/S0006297924030106

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