Cytotoxic oxindole derivatives: in vitro EGFR inhibition, pharmacophore modeling, 3D-QSAR and molecular dynamics studies.

Epidermal growth factor receptor (EGFR) is one of the vital protein targets in many solid tumors and is an attractive target for developing new drugs. In this study we have focused on elucidation of the mechanistic insights of cytotoxic potentials of oxindole derivatives using various in vitro and molecular modeling techniques. In vitro EGFR inhibition assay is performed with the potent cytotoxic oxindole compounds which are previously proved for their cytotoxic activity against breast cancer (MCF7) and ovarian cancer (SKVO3) cell lines. Molecular docking studies against kinase domain of EGFR protein revealed the probable interactions of oxindole derivatives. Pharmacophore modeling 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 ( r ² = 0.92, q ² = 0.80 and Pearson R  = 0.95). Molecular dynamic studies have revealed the conformational changes in the EGFR-compound 2complex during the 25 ns simulation time frame.