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Applied Biochemistry and Biotechnology

, Volume 186, Issue 1, pp 85–108 | Cite as

Ligand-Based Pharmacophore Screening Strategy: a Pragmatic Approach for Targeting HER Proteins

  • Nivya James
  • K. Ramanathan
Article

Abstract

Targeting ErbB family of receptors is an important therapeutic option, because of its essential role in the broad spectrum of human cancers, including non-small cell lung cancer (NSCLC). Therefore, in the present work, considerable effort has been made to develop an inhibitor against HER family proteins, by combining the use of pharmacophore modelling, docking scoring functions, and ADME property analysis. Initially, a five-point pharmacophore model was developed using known HER family inhibitors. The generated model was then used as a query to screen a total of 468,880 compounds of three databases namely ZINC, ASINEX, and DrugBank. Subsequently, docking analysis was carried out to obtain hit molecules that could inhibit the HER receptors. Further, analysis of GLIDE scores and ADME properties resulted in one hit namely BAS01025917 with higher glide scores, increased CNS involvement, and good pharmaceutically relevant properties than reference ligand, afatinib. Furthermore, the inhibitory activity of the lead compounds was validated by performing molecular dynamic simulations. Of note, BAS01025917 was found to possess scaffolds with a broad spectrum of antitumor activity. We believe that this novel hit molecule can be further exploited for the development of a pan-HER inhibitor with low toxicity and greater potential.

Keywords

NSCLC HER family PHASE GLIDE ADME 

Notes

Acknowledgments

The authors gratefully acknowledge VIT University, Vellore for the support through Seed Grant for Research.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12010_2018_2724_MOESM1_ESM.docx (34 kb)
ESM 1 (DOCX 33 kb)

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biotechnology, School of Bio Sciences and TechnologyVellore Institue of TechnologyVelloreIndia

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