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Updated: Aug 12, 2025
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Identification of potent EGFR-TKD inhibitors from NPACT database through combined computational approaches
Showkat Ahmad Mir1, Auwal Muhammad2, Archana Padhiary1
1School of Life Sciences, Sambalpur University, Jyoti Vihar, Odisha, India.
Abstract:
Cancer is the world's second leading cause of death, and there are no approved herbal therapies. The epidermal growth factor receptor tyrosine kinase (EGFR-TK) receptor is a transmembrane protein with eight domains that is found in almost every cancer type and plays an important role in abnormal cell cellular function and causes malignant outcomes. The current study aimed to virtually screen phytochemicals from the NPACT database against EGFR-TKD and also to identify potential inhibitors of this transmembrane protein among plant candidates for anticancer drug development. The docking scores of the chosen phytochemicals were compared with the control (erlotinib). Kurarinone, (2S)-2-methoxykurarnione, and Sophoraflavanone-G exhibited a stronger binding affinity of -18.102 kcal/mol, -14.243 kcal/mol, and -13.759 kcal/mol than erlotinib -12.783 kcal/mol. Moreover, several online search engines were used to predict ADME and toxicity. The drug-likeness of selected phytochemicals was higher than the reference (erlotinib). A 100 ns molecular dynamic (MD) simulation was also applied to the docked conformations to examine the stability and molecular mechanics of protein-ligand interactions. Furthermore, the calculated molecular mechanics Poisson Boltzmann surface area energy of (2S)-2-methoxykurarnione was found to be -129.555 ± 0.512 kJ/mol, which approximately corresponds to the free energy of the reference molecule -130.595 ± 0.908 kJ/mol. We identify phytoconstituents present in Sophora flavescens from the NPACT database, providing key insights into tyrosine kinase inhibition and may serve as better chemotherapeutic agents. Experimental validation is required to determine the anti-EGFR potency of the potent lead molecules discussed in this study.Communicated by Ramaswamy H. Sarma.
Insights
Researchers screened plant compounds for anticancer properties, identifying several potent inhibitors of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). These natural compounds show promise as novel chemotherapeutic agents against cancer.
Area of Science:
- Computational chemistry and drug discovery
- Molecular modeling and simulation
- Pharmacology and natural product chemistry
Background:
- Cancer is a leading global cause of death with limited herbal therapies.
- Epidermal growth factor receptor tyrosine kinase (EGFR-TK) is implicated in numerous cancers.
- Targeting EGFR-TK is a key strategy in cancer treatment.
Purpose of the Study:
- To virtually screen phytochemicals from the NPACT database against EGFR-TK.
- To identify potential plant-derived inhibitors for anticancer drug development.
- To evaluate the drug-likeness and stability of lead compounds.
Main Methods:
- Virtual screening using molecular docking against EGFR-TKD.
- Comparison of docking scores with erlotinib as a control.
- ADME/Toxicity prediction, molecular dynamics (MD) simulation, and MM/PBSA calculations.
Main Results:
- Kurarinone, (2S)-2-methoxykurarnione, and Sophoraflavanone-G showed superior binding affinity to EGFR-TK compared to erlotinib.
- Selected phytochemicals exhibited favorable drug-likeness and predicted ADME/Toxicity profiles.
- MD simulations confirmed the stability of protein-ligand interactions, with (2S)-2-methoxykurarnione showing comparable binding free energy to erlotinib.
Conclusions:
- Phytoconstituents from Sophora flavescens demonstrate significant potential as EGFR-TK inhibitors.
- Identified compounds may serve as lead molecules for developing novel chemotherapeutic agents.
- Experimental validation is necessary to confirm the anti-EGFR efficacy of these promising natural compounds.
