Abstract

A novel series of Benzothiazepine derivatives were designed and evaluated for epidermal growth factor receptor (EFGR) inhibitory potential by using various computational tools along with MTT assay based cell line studies towards anti-cancer activity. Our docking studies evidenced that all the present investigated twenty compounds have the potential to dock inside the active binding pocket of the EGFR Kinase domain with a binding energy in a range of -7.94 to -9.71 Kcal/mol. On the other hand, MTT assay based studies against DU145, MCF7 and HT29 cell lines showed good correlating results to our In-silico predictions. Moreover, all the designed compounds were predicted to be having promising ADMET parameters and found to be well in compliance with Lipinski’s rule of five along with no toxicology profile expect compound 7 based on Osiris property explorer predictions. Among all the twenty compounds tested, compound 9 is the best lead like molecule with -9.71 kcal/mol of binding energy with predicted IC50 value of 76.70 nano molar along with experimental IC50 values of 16±1, 27±1 and 28±1 in µg/ml for DU145, MCF7 and HT29 cell lines respectively. Molecular dynamic simulation studies for this compound 9 in complex with EGFR kinase domain has elucidated several interesting molecular level protein-ligand interactions with some of the important amino acid residues present at the active binding site of EGFR Kinase domain. Conclusively, novel designed compound 9 of the present study have shown promising anti- cancer potential worth considering for further evaluations.

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