مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
inhibitory effects of different phytochemicals on EGFR
inhibitory effects of different phytochemicals on EGFR
Aynaz Abedini Shoae,1,*Tara Azizi,2Sepideh Haghighi,3
1. Islamic Azad University Tehran Central Branch 2. Islamic Azad University Tehran Central Branch 3. Islamic Azad University Tehran Central Branch
Introduction: Receptor Tyrosine Kinases (RTKs) are a family of membrane-bound receptors that activate critical intracellular signaling pathways. EGFR (PDB ID: 5HG7), plays a vital role in regulating proliferation and survival in epithelial cells. Aberrant activation of EGFR often results from mutations, gene overexpression, or autocrine stimulation, and has been reported in various malignancies.
In this study, nine phytochemical compounds—kaempferol, myricetin, aloin, curcumin, piperine, bergamottin, gallic acid, hesperidin, and quercetin—were selected based on extensive reports of their anticancer and anti-inflammatory properties, as well as their native presence in Iran. Due to their polycyclic structures and reactive functional groups, these compounds exhibit high potential for interaction with the active site of EGFR’s kinase domain. Our approach involves molecular docking simulations using Chimera software and the AutoDock Vina algorithm to evaluate the interaction profiles and inhibitory potential of these compounds, aiming to identify the most potent inhibitor based on binding energy and stable interactions with the active site. The resulting insights may contribute to the rational design of natural inhibitors targeting EGFR and other RTKs.
Methods: The three-dimensional structure of the epidermal growth factor receptor (EGFR) tyrosine kinase was retrieved from the Protein Data Bank (PDB). Additionally, nine selected ligands were obtained from the PubChem database. Ligand and receptor preparation was performed using Chem3D and UCSF Chimera software, involving the addition of hydrogen atoms, assignment of Gasteiger partial charges, and molecular energy minimization to ensure accurate conformational geometry.
To identify the active site and predict potential binding pockets, two web-based servers—CASTp (version 3.0) and Proteins.Plus—were employed.
Molecular docking was carried out in two stages. Initially, blind docking was performed using AutoDock Vina via the UCSF Chimera interface to identify potential binding regions. Subsequently, PyMOL (version 2.5, Schrödinger LLC) was used to determine amino acid residues located within a 4.5 Å radius of each ligand. Based on these results, focused docking was conducted on the defined active region.
Results The docking analysis composes the evaluation of the binding modes, hydrogen bonding, and hydrophobic interactions between each compound and the tyrosine kinase receptor. To further validate the answers, the Protein-Ligand Interaction Profiler was utilized to assess the key interactions formed at the receptor’s active site. The docking scores and binding energies obtained from Chimera and AutoDock Vina were used to rank the compounds according to their potential inhibitory effects on the tyrosine kinase receptor.
Results: This study demonstrated that natural compounds with high binding affinities possess potential inhibitory activity against EGFR. The strong correlation between docking predictions obtained from software and web-based servers confirmed the high accuracy of the computational approach in identifying true active sites of the protein.Validation of these results through kinase activity assays highlights the effectiveness of this strategy for preliminary screening of anticancer agents.
Conclusion: These findings pave the way for the development of novel EGFR inhibitors, particularly targeting drug-resistant variants, and underscore the necessity of conducting cellular and in vivo experiments to establish the efficacy and safety of these compounds