Pyrrolo[3,2-d]pyrimidine derivatives as type II kinase insert domain receptor (KDR) inhibitors: CoMFA and CoMSIA studies

Int J Mol Sci. 2012;13(2):2387-2404. doi: 10.3390/ijms13022387. Epub 2012 Feb 22.

Abstract

Kinase insert domain receptor (KDR) inhibitors have been proved to be very effective anticancer agents. Molecular docking, 3D-QSAR methods, CoMFA and CoMSIA were performed on pyrrolo[3,2-d]pyrimidine derivatives as non-ATP competitive KDR inhibitors (type II). The bioactive conformation was explored by docking one potent compound 20 into the active site of KDR in its DFG-out inactive conformation. The constructed CoMFA and CoMSIA models produced statistically significant results with the cross-validated correlation coefficients q(2) of 0.542 and 0.552, non-cross-validated correlation coefficients r(2) of 0.912 and 0.955, and predicted correction coefficients r(2) (pred) of 0.913 and 0.897, respectively. These results ensure the CoMFA and CoMSIA models as a tool to guide the design of a series of new potent KDR inhibitors.

Keywords: CoMFA; CoMSIA; KDR inhibitor; Surflex-Dock; pyrrolo[3,2-d]pyrimidine derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology
  • Quantitative Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / chemistry
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • Pyrrolo(2,3-d)pyrimidine
  • Vascular Endothelial Growth Factor Receptor-2