Background:
The discovery of clinically relevant EGFR inhibitors for cancer therapy has proven
to be a challenging task. To identify novel and potent EGFR inhibitors, the quantitative structure-activity
relationship (QSAR) and molecular docking approach became a very useful and largely widespread technique
for drug design.
Methods:
We performed the in vitro cytotoxic activity on HEPG-2 cell line and earlier on MCF-7 and A
549 by using MTT assay method. The development of 3D QSAR model of N1,N4-bis(2-oxoindolin-3-
ylidene) succinohydrazides using the stepwise-backward variable methods to generate Multiple Linear Regression
method elucidates the structural properties required for EGFR inhibitory activity and also perform
the Molecular Docking studies on EGFR (PDB ID:1M17). Further, we analysed for Lipinski’s rule of five
to evaluate the drug-likeness and established in silico ADMET properties.
Results:
The resulting cytotoxicity (IC50) values ranged from 9.34 to 100 μM and compared with cisplatin
as a standard. Among the series of compounds, 6j showed good cytotoxic activity on HEPG-2 cell line with
9.34 μM, IC50 value. Most of the evaluated compounds showed good antitumor activity on HEPG-2 than
MCF-7and A549. The developed 3D QSAR Multiple Linear Regression models are statistically significant
with non-cross-validated correlation coefficient r2 = 0.9977, cross-validated correlation coefficient q2 =
0.902 and predicted_r2 = 0.9205. Molecular docking studies on EGFR (PDB ID: 1M17) results, compounds
6d, 6j and 6l showed good dock/PLP scores i.e. -81.28, -73.98 and -75.37, respectively, by interacting with
Leu-694, Val-702 and Gly-772 amino acids via hydrophobic and hydrogen bonds with Asn818 and Met-
769. Further, we analysed drug-likeness and established in silico ADMET properties.
Conclusion:
The results of 3D QSAR studies suggest that the electrostatic and steric descriptors influence
the cytotoxic activity of succinohydrazides. From the molecular docking studies, it is evident that
hydrophobic, hydrogen and Van Der Waal’s interactions determine binding affinities. In addition to this, druglikeness
and ADMET properties were analysed. It is evident that there is a correlation between the QSAR and
docking results. Compound 6j was found to be too lipophilic due to its dihalo substitution on isatin nucleus,
and can act as a lead molecule for further and useful future development of new EGFR Inhibitors.
2D, 3D QSAR AND MOLECULAR DOCKING STUDIES OF PYRAZOLYL-THIAZOLINONE DERIVATIVES AS EGFR INHIBITORS