Scoring of KDR kinase inhibitors: using interaction energy as a guide for ranking

Mol Divers. 2006 Aug;10(3):341-7. doi: 10.1007/s11030-006-9037-1. Epub 2006 Sep 27.

Abstract

Within a congeneric series of ATP-competitive KDR kinase inhibitors, we determined that the IC(50) values, which span four orders of magnitude, correlated best with the calculated ligand-protein interaction energy using the Merck Molecular Force Field (MMFFs(94)). Using the ligand-protein interaction energy as a guide, we outline a workflow to rank order virtual KDR kinase inhibitors prior to synthesis. When structural information of the target is available, the ability to score molecules a priori can be used to rationally select reagents. Our implementation allows one to select thousands of readily available reagents, enumerate compounds in multiple poses and score molecules in the active site of a protein within a few hours. In our experience, virtual library enumeration is best used when a correlation between computed descriptors/properties and IC(50) or K (i) values has been established.

MeSH terms

  • Binding Sites
  • Computer Simulation*
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Drug Interactions
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

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