Identification of Dual Inhibitors for EGFR and SRC Protein Kinases: A Molecular Docking Study

Abstract

Background: The human Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that has been found to cause a variety of cancers, especially lung cancer. SRC is a non-receptor tyrosine kinase whose expression correlates with cancer progression and metastatic disease by facilitating the actions of other signalling proteins like EGFR. It has been studied that interactions between EGFR and SRC may contribute to enhanced cancer development and resistance to already present inhibitors. So, there is a need to identify those molecules which can act as dual inhibitors for both EGFR and SRC protein kinases. In this study, molecular docking approach was used to identify such inhibitors. Objective: To identify dual inhibitors for EGFR and SRC proteins using Molecular Docking approach. Method and Results: Literature survey was performed in order to identify compounds that have the capacity to inhibit EGFR based on their IC50 value. 1433 compounds were identified from 121 research papers. The structures of these compounds were created using Marvin Sketch and PubChem and a library of these compounds was generated. Following that, we used the PDB database to search for 3D structure of the target protein. The SRC protein (PDB: 1Y57) was selected as the target protein. We then docked our target protein with the ligand library generated in the current study using Schrödinger’s Glide in order to identify potential ligands with the highest docking score and affinity for the SRC protein. The docking process was performed in 3 modes: HTVS, SP and XP. After molecular docking step, 18 compounds were identified which had higher docking score than the reference cocrystal. ADMET study was then performed to determine the pharmacokinetic characteristics of these ligands. Finally, 3 compounds were selected which had highest docking scores and showed 0 violations to Lipinski’s rule. VIII Conclusion: The current study has identified several compounds with higher docking score than the reference cocrystal as well as with 0 violations to Lipinski’s Rule of Five. Among these the top 3 compounds with the highest docking scores and best ADMET properties have been discussed in detail and these can also be taken forward for future research as potential dual inhibitors of EGFR and SRC protein kinases. Keywords: Lung cancer; Epidermal Growth Factor Receptor; epidermal growth factor; SRC protein; dual inhibitors; Molecular docking; ADMET