Der Pharma Chemica
Journal for Medicinal Chemistry, Pharmaceutical Chemistry, Pharmaceutical Sciences and Computational Chemistry

Abstract

Effect of an Indole-containing Pseudopeptide on Behavioral Despair Models in Mice: Supporting by Molecular Docking and Density Functional Theory Calculations

Author(s): Golnaz Mohebzadeh, Nahid Fakhraei, Keivan Akhtari, Golnoush Mohebzadeh, Saeed Balalaie, Keyumars Hassanzadeh, Ahmad Reza Dehpour

Aims: The study refers to application of a synthetic candidate containing an indole scaffold, 5f, in animal models of behavioral despair. Moreover, binding affinity and polarizability of 5f were calculated with molecular docking and density functional theory (DFT) study, respectively.

Materials and Methods: To compare, desipramine (DMI) (10 mg/kg, i.p.), a selective serotonin-norepinephrine reuptake inhibitor (SNRI) and fluoxetine (FLX) (10 mg/kg, i.p.), a selective serotonin reuptake inhibitor (SSRI) were employed. The binding affinity of 5f, FLX and DMI to LeuTa, a leucine tranporter as a homologous protein to monoamine, were evaluated. Also, polarizability of 5f was compared using DFT method. The neuroprotective effect of 5f on behavioral despair was evaluated using forced-swim and tail suspension tests in male mice. The drugs were injected intraperitoneally (i.p.) 30 minutes before the tests.

Results: 5f (2.5, 5, 10 mg/kg) significantly reduced the immobility behavior in a dose-dependent manner in the behavioral tests. Moreover, no significant changes in locomotor activity of the animals were detected. In addition, in line with the experimental results, docking demonstrated that 5f-LeuTAa complex has the highest bonding energy comparable with DMI. Moreover, DFT study showed the highest polarizability for 5f. Further, it showed a high lipophilicity. 5f had higher potency in the behavioral tests compared to the antidepressants; however, it was more structurally similar to DMI. 5f was probably capable to reduce behavioral despair lowering the immobility figure.

Conclusion: Demonstrating a high polarizability and having the highest bonding energy of docked 5f-LeuTAa complex comparable with DMI along, 5f probably has the potential to make more serotonin and norepinephrine available.


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