Pharmacophore Based Design and Development of Probable Multi Tyrosine Kinase Inhibitors from the 3D Crystal Structure of Gefitinib – A Drug Used in the Treatment of NSCLC

Gefitinib (ZD1839) a selective EGFR inhibitor approved by the FDA is used to treat metastatic non-small cell lung cancer in humans. So, screening compounds having similar pharmacophoric features like Gefitinib with multi targeted effect to restrict drug resistance is the main motivation of this work. A pharmacophore was generated from the crystal structure of Gefitinib-EGFR complex with several pharmacophoric features. May Bridge database contains 51,663 drug like compounds were taken for virtual screening and according to the Fit value best hit compound (Hit-1) was chosen for lead optimization to improve pharmacophoric features. Optimized Leads were further screened with same pharmacophoric features of Gefitinib-EGFR complex to obtained better Hit compounds i.e. methyl 2-((7-methoxy-6-(3-(piperazin-1-yl) propoxy) quinazolin-4-yl) thio) acetate (Hit-2) and compound methyl 2-((7-methoxy-6-(3-morpholinopropoxy) quinazolin-4-yl) thio) acetate (Hit-3) with high Fit value (4.83269 and 4.76094). Finally, their ADMET prediction and binding study with EGFR and VEGFR-2 were performed to conclude multitargeted effect.