Comparative study of the effects of Sertraline and Escitalopram on EGFR protein using molecular docking method
Comparative study of the effects of Sertraline and Escitalopram on EGFR protein using molecular docking method
Mohadeseh Farahani,1,*Yekta Mahmoudi Naraghi,2
1. Modern Technologies science, Tehran Medical Sciences Islamic Azad University, Tehran, Iran 2. Modern Technologies science, Tehran Medical Sciences Islamic Azad University, Tehran, Iran
Introduction: Glioblastoma is the most malignant of the glial tumors and is associated with extremely poor survival. The majority of GBMs have been identified to harbor genetic events in receptor tyrosine kinase signaling pathways. Among the most relevant pathways are those engaged by activation of epidermal growth factor receptor(EGFR). EGFR amplification is common in GBMs,and together with mutation,rearrangement, and/or altered splicing, genetic alteration of EGFR at large has been observed in 57% of these tumors. Activation of EGFR signaling is triggered by ligand-induced receptor dimerization following which the tyrosine residues presentin the intrinsic kinase domain of one receptor cross-phosphorylate specific residues in the C-terminal tail of the partnering receptor, thus providing a scaffold for the recruitment of effector proteins.Sertraline is a member of tetralins, a secondary amino compound and a dichlorobenzene. Sertraline is a popular antidepressant medication commonly known as a selective serotonin reuptake inhibitor (SSRI).Escitalopram (C20H21FN2O) is a selective serotonin reuptake inhibitor (SSRI) and the S-enantiomer of racemic [citalopram]. It is used to restore serotonergic function in the treatment of depression and anxiety.
Methods: First, we enter the uniprot protein database and search the desired protein, which is EGFR, we select the corresponding human protein from the displayed results. Among the results, we select the protein with more position, less chain and higher resolution. Then we click on the RCSB PDB section and in the next step, we download the desired protein in 3D mode and in PDB format. We also enter the drugs in the Pubchem site and download their 3D mode in SDF format.In order to modify the protein, we enter the Chimera software. We load the EGFR protein into the program in PDB format. We Choose the select section and then choose chain, we can see that the EGFR protein has 5 chains. We compare chains and remove small chains with lower density. In this case, we decided to perform molecular docking on the two larger chains A and B. In the structure section,we check the presence of ions and remove them if existed. At this stage,in the Tools section we apply changes such as removing solvents, removing non complex ions, adding hydrogen and adding charge. We perform these steps for both A and B chains separately and download the modified protein converted to PDBqt form.After that, we enter the PyRxb software and the load chain A of the modified protein from the load molecule section and apply the make macromolecule option to it.Then we import sertraline and Escitalopram drugs respectively from the import section and choose Minimize all and then convert all to Autodock Ligand option to convert the two drugs from SDF form to PDBqt charged form.Meanwhile, through the deepsite, we find the exact coordinates and active site of each chain.Chain A has the best active site at coordinates [X:103.1 Y:65.8 Z:43.7] and chain B at coordinates [X:63.4 Y:51.8 Z:54.7].We go back to PyRx software, select Vina Wizard, click on start, press Forward in the next step, and in this section manually enter the coordinates obtained from deepsite and start docking. We perform all these steps for chain B after then we get the docking results.
Results: After performing molecular docking on the A and B chains of EGFR protein and on both drugs We can see that RMSD in all four results is 0 and binding affinity in all results are more negative than -5.Our best binding affinity for chain A and Sertraline is -6.6.Best binding affinity for chain A and Escitalopram is -6.1.Best binding affinity for chain B and Sertraline is -6.3.For chain B and Escitalopram binding affinity is -5.9
Conclusion: These results show that both drugs are successfully bound to EGFR protein, but according to the results, Sertraline can establish a stronger connection, better bind to the EGFR protein and therefore be more effective in the treatment of glioblastoma.