title: In silico exploration of c-KIT inhibitors by pharmaco-informatics methodology: pharmacophore modeling, 3D QSAR, docking studies, and virtual screening.
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 (R2 = 0.9378, Q2 = 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.
authors.affiliation: Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Dist-Dhule, Shirpur, Maharashtra, 425 405, India. prashantniperk@gmail.com.
authors.forename: Prashant
authors.initials: P
authors.lastname: Chaudhari
authors.affiliation: Department of Pharmaceutical Chemistry, H. R. Patel Institute of Pharmaceutical Education and Research, Dist-Dhule, Shirpur, Maharashtra, 425 405, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bari
mesh_terms: D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit
keywords: 3D QSAR; Docking; Indolin-2-one; Pharmacophore; ZINC; c-KIT inhibitors