Statement of the Problem: Epidermal growth factor receptor (EGFR) is one of the over expressed and crucially targeted protein in many solid tumours and is a fascinating target for developing new drugs: Scarcity and need of effective drugs in present therapy: In the current study we have focussed on elucidation of the mechanistic insights of cytotoxic potentials of oxindole derivatives by performing in vitro EGFR inhibition assay of cytotoxic oxindole compounds which are earlier proved for their cytotoxic activity against breast cancer (MCF7) and ovarian cancer (SKVO3) cell lines and performing various molecular modelling techniques such as Docking, Pharmacophore modelling, 3D QSAR and Molecular dynamics studies. Findings: In vitro EGFR inhibition assay revealed that compounds with substantial cytotoxic activity against breast cancer (MCF7) and ovarian cancer (SKVO3) cell lines showed potential EGFR Inhibition. Molecular docking studies against kinase domain of EGFR protein indicated the probable interactions of oxindole derivatives. Pharmacophore modelling studies had identified a pharmacophore model with three hydrogen bond acceptors and three aromatic rings (AAARRR.1003) as a potential model for cytotoxic activity against MCF7 cell lines and validated through 3D QSAR studies resulting in superior regression scores (r2 = 0.92, q2 = 0.80 and Pearson R = 0.95). Molecular dynamic studies revealed the conformational changes in the EGFR-compound 1b complex and EGFR-compound 1c complex during the 25 ns simulation time frame. Further simulations with longer time period may provide deeper insights of ligand interactions in the protein environment.Conclusion & Significance: Compound 1b has performed potential in vitro EGFR inhibition among the title compounds, which is supported by its molecular dynamics simulations with EGFR protein. Hence it is noteworthy to use compound 1b as a new scaffold for further development of multifunctional compounds.
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