EGFR tyrosine kinase inactivation by Withacoagulin-induced conformational shift

Epidermal growth factor receptor (EGFR), a transmembrane protein, plays a vital role in regulating cell proliferation, survival, differentiation, and migration in various cellular processes. Overexpression of EGFR is associated with many malignancies, making it a viable target for the development of anticancer drugs. Natural molecules from medicinal plants present an appealing option for treating life-threatening diseases like cancer. In light of this, the main objective of the present study is to find the potent phytoconstituent of widely recognized medicinal plants that can inhibit the EGFR tyrosine kinase (EGFR TK). We have created a database of 2000 such phytoconstituents along with the standard drug Gefitinib for comparison. A total of 215 molecules exhibited more favorable docking scores than the cut-off -7.4 kcal/mol (docking score of Gefitinib). From the ADMET and binding analysis, we found that M31 (Withacoagulin), M39 (LTS0153006), and M40 (Somniferanolide) are the most promising candidates, with suitable drug-like properties and favorable interaction with EGFR TK. Unlike the standard drug, which exhibits hepatotoxicity, these are predicted to lack hepatotoxicity. Further, molecular dynamics (MD) simulation and binding free energy calculations reveal that Withacoagulin binds more strongly to EGFR TK than other compounds and induces conformational changes that shift the protein more towards its inactive-like state. Hence, this can be used as a potential therapeutic for cancer associated with EGFR overexpression. However, to ensure its efficacy, wet-lab experiments and clinical trials are recommended, which could suggest that Withacoagulin is a novel anticancer drug.