Identification of Novel EGFR Inhibitors for the Targeted Therapy of Colorectal Cancer Using Pharmacophore Modelling, Docking, Molecular Dynamic Simulation and Biological Activity Prediction


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Abstract

Background:Colorectal cancer (CRC) is considered the second deadliest cancer in the world. One of the reasons for the occurrence of this cancer is the deregulation of the Epidermal Growth Factor Receptor (EGFR), which plays a critical role in regulating cell division, persistence, differentiation, and migration. The overexpression of the EGFR protein leads to its dysregulation and causes CRC.

Objective:Hence, this work aims to identify and validate novel EGFR inhibitors for the treatment of colorectal cancer employing various computer aided techniques such as pharmacophore modeling, docking, molecular dynamic simulation and Quantitative Structure-Activity Relationship (QSAR) analysis.

Methods:In this work, a shared-featured ligand-based pharmacophore model was generated using the known inhibitors of EGFR. The best model was validated and screened against ZincPharmer and Maybridge databases, and 143 hits were obtained. Pharmacokinetic and toxicological properties of these hits were studied, and the acceptable ligands were docked against EGFR. The best five protein-ligand complexes with binding energy less than -5 kcal/mol were selected. The molecular dynamic simulation studies of these complexes were conducted for 100 nanoseconds (ns), and the results were analyzed. The biological activity of this ligand was calculated using QSAR analysis.

Results:The best complex with Root Mean Square Deviation (RMSD) 3.429 Å and Radius of Gyration (RoG) 20.181 Å was selected. The Root Mean Square Fluctuations (RMSF) results were also found to be satisfactory. The biological activity of this ligand was found to be 1.38 µM.

Conclusion:This work hereby proposes the ligand 2-((1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)oxy)-N- (1H-indol-4-yl)acetamide as a potential EGFR inhibitor for the treatment of colorectal cancer. The wet lab analysis must be conducted, however, to confirm this hypothesis.

About the authors

Amrutha Krishnan K.

Department of Applied Science and Humanities, Sahrdaya College of Engineering and Technology,, Affiliated to APJ Abdul Kalam Technological University,

Author for correspondence.
Email: info@benthamscience.net

Sudha George Valavi

Department of Applied Science and Humanities, Sahrdaya College of Engineering and Technology, Affiliated to APJ Abdul Kalam Technological University

Email: info@benthamscience.net

Amitha Joy

Department of Biotechnology, Sahrdaya College of Engineering and Technology, Affiliated to APJ Abdul Kalam Technological University

Email: info@benthamscience.net

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