The potential of phytochemicals against epidermal growth factor receptor tyrosine kinase (EGFRK): an insight from molecular dynamic simulations

Abstract

Cancer is an umbrella term used to define various diseases with abnormal cell proliferation at the focal point. According to the WHO, cancer is the leading cause of death worldwide, with lung cancer being the second most common perpetrator after breast cancer. There are several proteins acting in harmony that lead to cancer. EGFR has been identified as one of the proteins that is linked to cell division, even when it is cancerous in nature. Cancer can be treated using therapeutic agents that target EGFR or their signaling networks. Available drugs that could inhibit EGFR have acquired resistance in most cases and multiple side effects on the human body. That is why phytochemicals are being studied for their role in this case. Around 8000 compounds were retrieved from our previously created phytochemdb database for their drug activity, and the 3D protein structure was collected from the protein data bank. The selected dataset of ligands was virtually screened through HTVS, SP, and XP to retain the top 4 hits. Molecular dynamics revealed the stability and flexibility of protein-(selected)ligand interactions. The non-bond interactions of each of the compounds with EGFR, such as Gossypetin interacting with active site MET769 and ASP831; Muxiangrine III interacting with MET769 and ASP831; Quercetagetin showing non-bonded interactions with GLU738, GLN767, and MET769 for >100% of the simulation timeframe These findings suggest further research into these compounds, which can yield a potential phytochemical drug against cancer.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cancer
• phytochemicals
• EGFRK
• MD simulation

Authors contribution

F.B.R. wrote the manuscript, interpreted the data and results, and compiled information from co-authors. B.H.L. was responsible for the ligand library and protein preparation. He also performed molecular docking and screening along with MMGBSA. S.J.J. and A.K. analyzed the EGFR binding site interaction with different ligands and transcribed the docking methodology used here. They also processed all the figures (related to molecular docking) presented here. N.L., M.S., and A.R. reviewed literature regarding the necessity of novel drug design and the possible role of phytochemicals against EGFR. They also studied EGFR binding sites and phosphorylation mechanisms for further investigation. S.K.H. performed MD simulation and interpreted data from the MD trajectory.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study received a small grant from A.K. Azad for the purchase of a Google Collaborate Pro server. We used this server for multiple force field-based conformational sampling of EGFR protein-ligand complexes. Finally, we had employed Desmond for triplicate runs.