Molecular Stability Assessment of Second-Generation EGFR Inhibitors in Interaction with Wild-Type Protein: A Molecular Dynamics Simulation Study

Mohammadi Mousavi, Sayed Sadegh; Arab, Seyed Shahriar

doi:10.48311/biot.2025.27534

Molecular Stability Assessment of Second-Generation EGFR Inhibitors in Interaction with Wild-Type Protein: A Molecular Dynamics Simulation Study

Document Type : Original Research

Authors

Sayed Sadegh Mohammadi Mousavi

Seyed Shahriar Arab

Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University

https://doi.org/10.48311/biot.2025.27534

Abstract

Epidermal growth factor receptor (EGFR) is one of the most important tyrosine kinase receptors that plays a key role in regulating cellular processes and the progression of many cancers, including lung cancer. In this study, the effects of second-generation EGFR inhibitors, including Afatinib, Dacomitinib, and Neratinib, as well as the candidate drugs Canertinib and Poziotinib, on wild-type EGFR were investigated using molecular dynamics (MD) simulations. For this purpose, structural data were collected and analyzed from reliable databases. Molecular docking studies led to the identification of drug binding sites, and molecular dynamics (MD) simulations under physiological conditions investigated stability and ligand-protein interactions. The parameters such as RMSD, radius of gyration (Rg), SASA, and hydrogen bonds were calculated to evaluate the stability of the protein-ligand complex. The results of the MMPBSA analysis showed that Neratinib, with the lowest free energy of binding (ΔG), has a higher binding affinity to EGFR and demonstrated greater stability during the simulation. Also, the principal component analysis (PCA) showed that the EGFR-Neratinib complex has less dynamics and occupies less phase space, which indicates more stability of this complex.
These results show that of all the compounds studied, Neratinib may be the most potent and promising candidate in advancing combination therapies against EGFR.

Keywords

EGFR Wild-Type

Second-Generation EGFR Inhibitors

Molecular Dynamics Simulation

MMPBSA Analysis

Neratinib

Subjects

Bioinformatics

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