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Cytotoxic oxindole derivatives: in vitro EGFR inhibition, pharmacophore modeling, 3D-QSAR and molecular dynamics
Sasikala Maadwar1,2, Rajitha Galla1
1Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam, Tirupati, India.
Abstract:
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 (r2 = 0.92, q2 = 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.
Insights
Oxindole derivatives show cytotoxic potential against cancer cells by inhibiting the epidermal growth factor receptor (EGFR). Molecular modeling studies elucidate their mechanism of action and interactions with EGFR.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Oncology
Background:
- Epidermal growth factor receptor (EGFR) is a key target in solid tumor treatment.
- Oxindole derivatives have demonstrated cytotoxic activity against breast and ovarian cancer cell lines.
Purpose of the Study:
- To investigate the mechanistic insights into the cytotoxic potential of oxindole derivatives.
- To explore their interaction with the epidermal growth factor receptor (EGFR).
Main Methods:
- In vitro EGFR inhibition assays.
- Molecular docking and pharmacophore modeling.
- 3D Quantitative Structure-Activity Relationship (QSAR) studies.
- Molecular dynamic simulations.
Main Results:
- Oxindole derivatives showed potent EGFR inhibition.
- Molecular docking identified probable interactions with the EGFR kinase domain.
- A pharmacophore model (AAARRR.1003) was identified for cytotoxic activity.
- 3D QSAR studies validated the model with high regression scores (r² = 0.92, q² = 0.80).
- Molecular dynamics revealed conformational changes in the EGFR-compound complex.
Conclusions:
- Oxindole derivatives represent promising EGFR inhibitors for cancer therapy.
- Computational modeling provides valuable insights for designing novel anti-cancer agents targeting EGFR.
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