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Superimposition in PyMOL, visualization of the 3D model of the ligand in Discovery Studio (ligand-amino acid interaction, category and type of bonds, their distances), and lastly ADMET properties were checked to select the best candidates. Out of all drugs, Glimepiride, Danagliptin, Omarigliptin passed all the requirements. Their binding affinities were -9.7, -9.1 and -8.4 (kcal/mol) respectively. These drugs were chosen as they showed higher binding affinities than the standard one (Mirtazapine: -8.00 kcal/mol). Among the natural molecules, curcumin was selected (binding affinity: -9.5). These molecules were selected for further evaluation as they superimposed quite well. The 3D model of the complex was then visualized through Discovery Studio where amino acid-ligand interaction, their bond type and category, their distance were evaluated. Some of the amino acids that were common between the standard and the combination were GLU185, ASP328, GLU329, ARG172 and LEU176.
The category of the bonds was mostly: hydrophobic and hydrogen bonds. The distance range was kept 2 to 5. Lastly, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) properties of each candidate were predicted by admetSAR. The factors that were investigated were blood brain barrier, human intestinal absorption, caco-2 permeability, AMES toxicity, carcinogens etc. Denagliptin was discarded as it proved to cause long-term toxicity. In addition, Glimepiride was chosen the best possible synthetic drug over Omarigliptin. Among the natural molecules, Curcumin was the chosen as the best option. Thus, this in silico study paved the path to repurpose existing approved drugs and natural molecule for the treatment of major depressive disorder.
4.2 Conclusion
Through in-silico molecular docking screening, this study showed that Glimepiride, an existing approved anti-diabetic synthetic drug and Curcumin, a natural small molecule have anti-depressant properties. They both showed higher binding affinities than the standard drug
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properties were better than the standard drug. Hence, it can be said that, this study put forward a possibility of new drug development for depression.
4.3 Future work
This study was an in-silico study, hence, further in-vitro and in-vivo study should be conducted to confirm the effectivity of the proposed drugs. Additionally, molecular dynamic simulation should be done to see the physical movements of the protein and ligand while binding, their duration of binding and their specific binding sites.
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