Studies on the Dual Activity of EGFR and HER-2 Inhibitors Using Structure-Based Drug Design Techniques

Int J Mol Sci. 2018 Nov 23;19(12):3728. doi: 10.3390/ijms19123728.

Abstract

HER-2 and EGFR are biological targets related to the development of cancer and the discovery and/or development of a dual inhibitor could be a good strategy to design an effective drug candidate. In this study, analyses of the chemical properties of a group of substances having affinity for both HER-2 and EGFR were carried out with the aim of understanding the main factors involved in the interaction between these inhibitors and the biological targets. Comparative analysis of molecular interaction fields (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were applied on 63 compounds. From CoMFA analyses, we found for both HER-2 (r² calibration = 0.98 and q²cv = 0.83) and EGFR (r² calibration = 0.98 and q²cv = 0.73) good predictive models. Good models for CoMSIA technique have also been found for HER-2 (r² calibration = 0.92 and q²cv = 0.74) and EGFR (r² calibration = 0.97 and q²cv = 0.72). The constructed models could indicate some important characteristics for the inhibition of the biological targets. New compounds were proposed as candidates to inhibit both proteins. Therefore, this study may guide future projects for the development of new drug candidates for the treatment of breast cancer.

Keywords: CoMFA; CoMSIA; EGFR; HER-2; cancer; docking; drug design; dual inhibitor.

MeSH terms

  • Binding Sites
  • Drug Design*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / chemistry*
  • Humans
  • Models, Molecular*
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Quantitative Structure-Activity Relationship*
  • Reproducibility of Results

Substances

  • Protein Kinase Inhibitors
  • ErbB Receptors