Pharmacophore modelling, molecular docking and virtual screening for EGFR (HER 1) tyrosine kinase inhibitors

Abstract

A pharmacophore model has been developed using diverse classes of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors useful in the treatment of human tumours. Among the top 10 generated hypotheses, the second hypothesis, with one hydrogen bond acceptor, one ring aromatic and three hydrophobic features, was found to be the best on the basis of Cat Scramble validation as well as test set prediction (r _training = 0.89, r _test = 0.82). The model also maps well to the external test set molecules as well as clinically active molecules and corroborates the docking studies. Finally, 10 hits were identified as potential leads after virtual screening of ZINC database for EGFR TK inhibition. The study may facilitate the designing and discovery of novel EGFR TK inhibitors.

Keywords:

• EGFR tyrosine kinase
• HER 1
• Discovery Studio
• pharmacophore
• docking
• virtual screening

Acknowledgements

The technical assistance of Mr A.S. Kushwaha during this work is gratefully acknowledged. Two authors (AKG and SSB) acknowledge CSIR, New Delhi, while one (VMB) acknowledges ICMR, New Delhi, for financial support. The CDRI communication number of this manuscript is 7843.