The unbinding studies of vascular endothelial growth factor receptor-2 protein tyrosine kinase type II inhibitors

J Mol Graph Model. 2015 Jun:59:130-5. doi: 10.1016/j.jmgm.2015.04.011. Epub 2015 May 2.

Abstract

Vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase has two conformations, active and inactive conformations. Type II inhibitors bind to inactive conformation. It has two possible binding/unbinding paths. To explore the unbinding path of inhibitor 01-435 that was generated by fragment build in the binding pocket of VEGFR-2, molecular dynamics (MD) simulation was performed on the crystal structure of VEGFR-2 in complex with 01-435, then steered molecular dynamics (SMD) simulation was executed on the crystal structure of VEGFR-2 in complex with 01-435. Pull force, van der Waals and electrostatic interaction along the two paths were calculated by using SMD simulation. The SMD simulation results indicate that the more favorable path for inhibitor dissociation is along with the traditional ATP-channel rather than the allosteric-pocket-channel, which is mainly due to the less electrostatic interaction that the ligand suffers during dissociation process along the traditional ATP-channel.

Keywords: Electrostatic interaction; Fragment build; Pull force; SMD; VEGFR-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ligands
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / chemistry*
  • Static Electricity
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / chemistry*

Substances

  • Ligands
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor Receptor-2