Computational Studies of bis-2-Oxoindoline Succinohydrazides and their In Vitro Cytotoxicity

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Author(s): Ravi Jarapula, Vishnu Nayak Badavath, Shriram Rekulapally, Sarangapani Manda*.

Journal Name: Current Computer-Aided Drug Design

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Abstract:

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 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 to elucidate 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 resulted cytotoxicity (IC50) values range from 9.34 to 100µM 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, the compounds 6d, 6j and 6l showed good dock/PLP scores i.e.-81.28, -73.98 and -75.37 by interacting with Leu-694, Val-702and 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 electrostatic and steric descriptors influence the cytotoxic activity of succinohydrazides. From the molecular docking studies, it is evident that hydrophobic, hydrogen and Vander Waal’s interactions determine binding affinities. In addition to this, drug likeness & 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 their dihalo substitution on isatin nucleus, can be acts a lead molecule for further and useful for future development of new EGFR Inhibitors.

Keywords: Bis-2-Oxoindoline succinohydrazide derivatives, Cytotoxicity, 3D QSAR-MLR, EGFR, ADMET, Molecular docking studies.

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(E-pub Ahead of Print)
DOI: 10.2174/1573409915666190117122139
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