An efficient tool for identifying inhibitors based on 3D-QSAR and docking using feature-shape pharmacophore of biologically active conformation--a case study with CDK2/cyclinA

Eur J Med Chem. 2008 Dec;43(12):2807-18. doi: 10.1016/j.ejmech.2007.10.016. Epub 2007 Oct 22.

Abstract

This study proposes a fast and efficient approach for identifying novel inhibitors when the biologically active conformation of an inhibitor is known. The present study was carried out with CDK2/CyclinA inhibitors. The co-crystal structure of the most active ligand with CDK2/CyclinA was converted into a feature-shape query. This query served three purposes (i) alignment of molecules to generate 3D-QSAR model, (ii) rigid docking to the active site using GOLD, (iii) extracting hits from databases. A statistically valid 3D-QSAR (r(2)=0.867, q(2)=0.887) with good external set prediction (r(pred)(2)=0.890) was obtained. The docked poses were analyzed based on their interaction with hinge region (Glu81-Leu83) of CDK2. A reasonably good consensus score was generated using 11 scoring functions. The developed model was then successfully used to identify potential leads for CDK2/CyclinA inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Computer Simulation*
  • Crystallography, X-Ray
  • Cyclin A / antagonists & inhibitors*
  • Cyclin A / chemistry
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 2 / chemistry
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Chemical*
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Quantitative Structure-Activity Relationship*
  • Stereoisomerism

Substances

  • Cyclin A
  • Enzyme Inhibitors
  • Pyrazoles
  • Cyclin-Dependent Kinase 2