Discovery of Novel Small-Molecule Tyrosine Kinase Inhibitors of Egfr and Her-2 by Ligand Based Virtual Screening.

Abnormal signaling from the Protein tyrosine kinase (PTK) like receptor tyrosine kinase and intracellular tyrosine kinase can lead to diseases such as cancer especially breast cancer, non-small cell lung cancer, chronic myeloid leukaemia etc. Various protein tyrosine kinase inhibitors are available in pharmaceutical market but they face poor bioavailability, severe toxicities and drug-resistant cancers which promote for development of better lead as a drug molecule. In this study we report the design and development of a novel protein tyrosine kinase inhibitor on the basis of in-silico studies. Identification of novel EGFR and HER2 inhibitors with improved therapeutics index was performed with a highly correlating (r=0.820) ligand-based pharmacophore model (Hypo1) in this study. Hypo1 was generated from a training set of 27 compounds with EGFR/HER2 inhibitory activity and well-validated hypothesis model was subsequently used as a 3D query to screen ~200000 compounds in a total of three databases which consist of CHEMBL, SPECS and Maybridge libraries. Further, these compounds were analyzed for compliance with Lipinski’s rule of five, Veber rule for drug-likeness evaluation and optimum Absorption, Distribution, Metabolism, Excretion and Toxicity parameters by employment of drug discovery studio software. The selected compounds were then subjected to molecular docking to discern their molecular interactions at the ATP binding site of HER2 and EGFR proteins. The findings thus presented would be an important starting point towards the development of novel EGFR & HER2 inhibitors using well-validated computational techniques.