Identification of curcumin derivatives as human glyoxalase I inhibitors: A combination of biological evaluation, molecular docking, 3D-QSAR and molecular dynamics simulation studies

Bioorg Med Chem. 2011 Feb 1;19(3):1189-96. doi: 10.1016/j.bmc.2010.12.039. Epub 2010 Dec 22.

Abstract

Several recent developments suggest that the human glyoxalase I (GLO I) is a potential target for anti-tumor drug development. In present study, a series of curcumin derivatives with high inhibitory activity against human GLO I were discovered. Inhibition constant (K(i)) values of compounds 8, 9, 10, 11 and 13 to GLO I are 4.600μM, 2.600μM, 3.200μM, 3.600μM and 3.600μM, respectively. To elucidate the structural features of potent inhibitors, docking-based three-dimensional structure-activity relationship (3D-QSAR) analyses were performed. Satisfactory agreement between experiment and theory suggests that comparative molecular similarity index analysis (CoMSIA) modeling exhibit much better correlation and predictive power. The cross-validated q(2) value is 0.638 while no-validation r(2) value is 0.930. Integrated with docking-based 3D-QSAR CoMSIA modeling, molecular surface property (electrostatic and steric) mapping and molecular dynamics simulation, a set of receptor-ligand binding models and bio-affinity predictive models for rational design of more potent inhibitors of GLO I are established.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Curcumin / analogs & derivatives*
  • Curcumin / analysis
  • Curcumin / chemical synthesis
  • Curcumin / chemistry
  • Curcumin / metabolism
  • Curcumin / pharmacology
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Genetic Vectors
  • Humans
  • Inhibitory Concentration 50
  • Lactoylglutathione Lyase / antagonists & inhibitors*
  • Lactoylglutathione Lyase / chemistry
  • Lactoylglutathione Lyase / metabolism
  • Models, Molecular
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Molecular Targeted Therapy
  • Plasmids
  • Protein Binding
  • Protein Conformation
  • Quantitative Structure-Activity Relationship*

Substances

  • Enzyme Inhibitors
  • Lactoylglutathione Lyase
  • Curcumin