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Molecular Diversity

, Volume 20, Issue 1, pp 41–53 | Cite as

In silico exploration of c-KIT inhibitors by pharmaco-informatics methodology: pharmacophore modeling, 3D QSAR, docking studies, and virtual screening

  • Prashant Chaudhari
  • Sanjay Bari
Full-Length Paper

Abstract

c-KIT is a component of the platelet-derived growth factor receptor family, classified as type-III receptor tyrosine kinase. c-KIT has been reported to be involved in, small cell lung cancer, other malignant human cancers, and inflammatory and autoimmune diseases associated with mast cells. Available c-KIT inhibitors suffer from tribulations of growing resistance or cardiac toxicity. A combined in silico pharmacophore and structure-based virtual screening was performed to identify novel potential c-KIT inhibitors. In the present study, five molecules from the ZINC database were retrieved as new potential c-KIT inhibitors, using Schrödinger’s Maestro 9.0 molecular modeling suite. An atom-featured 3D QSAR model was built using previously reported c-KIT inhibitors containing the indolin-2-one scaffold. The developed 3D QSAR model ADHRR.24 was found to be significant (\(R^{2}=0.9378, Q^{2}=0.7832\)) and instituted to be sufficiently robust with good predictive accuracy, as confirmed through external validation approaches, Y-randomization and GH approach [GH score 0.84 and Enrichment factor (E) 4.964]. The present QSAR model was further validated for the OECD principle 3, in that the applicability domain was calculated using a “standardization approach.” Molecular docking of the QSAR dataset molecules and final ZINC hits were performed on the c-KIT receptor (PDB ID: 3G0E). Docking interactions were in agreement with the developed 3D QSAR model. Model ADHRR.24 was explored for ligand-based virtual screening followed by in silico ADME prediction studies. Five molecules from the ZINC database were obtained as potential c-KIT inhibitors with high in -silico predicted activity and strong key binding interactions with the c-KIT receptor.

Graphical abstract

Keywords

c-KIT inhibitors Indolin-2-one  Pharmacophore  3D QSAR ZINC Docking 

Notes

Acknowledgments

Authors are thankful to Prof. Sanjay J. Surana, Principal, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, India, for availing the facility to carry out the computational work and his valuable support. Authors are also grateful to the North Maharashtra University, Jalgaon, Maharashtra, for providing financial assistance under the scheme “Vice chancellor Research Motivation Scheme (VCRMS),” Sanction No. NMU/11A/VCRMS/Budget-2014-15/Pharmacy-15/170/2015.

Compliance with ethical standards

Conflicts of Interest

Corresponding author Prashant J. Chaudhari presented a part of this manuscript at ‘State Level AVISHKAR-2014: The inter-university research convention, Maharashtra’.

Supplementary material

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Supplementary material 1 (docx 189 KB)
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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Pharmaceutical ChemistryR. C. Patel Institute of Pharmaceutical Education and ResearchShirpurIndia
  2. 2.Department of Pharmaceutical ChemistryH. R. Patel Institute of Pharmaceutical Education and ResearchShirpurIndia

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