Pharmacophore-based 3D-QSAR of HIF-1 inhibitors

Arch Pharm Res. 2009 Mar;32(3):317-23. doi: 10.1007/s12272-009-1301-3. Epub 2009 Apr 23.

Abstract

(Aryloxyamino)benzoic acids and nicotinic/isonicotinic acids represent an important new class of small molecules that inhibit the activation of hypoxia-inducible factor (HIF)-1. In order to understand the factors affecting inhibitory potency of HIF-1 inhibitors, 3 dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed. Since no receptor structure are available, the pharmacophore-based alignment was used for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The CoMFA and CoMSIA models gave reasonable statistics (CoMFA: q(2) = 0.564, r(2)=0.945; CoMSIA: q(2) = 0.575, r(2)=0.929). Both CoMFA and CoMSIA results indicate that the steric interaction is a major factor, while CoMSIA suggests importance of hydrogen bonding. These findings about steric and H-bonding effects can be useful to design new inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Benzoates / chemistry
  • Computer-Aided Design*
  • Drug Design*
  • Hydrogen Bonding
  • Hypoxia-Inducible Factor 1 / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1 / chemistry*
  • Imaging, Three-Dimensional*
  • Isonicotinic Acids / chemistry
  • Least-Squares Analysis
  • Ligands
  • Models, Molecular*
  • Molecular Structure
  • Nicotinic Acids / chemistry
  • Protein Conformation
  • Quantitative Structure-Activity Relationship*
  • Reproducibility of Results

Substances

  • Antineoplastic Agents
  • Benzoates
  • Hypoxia-Inducible Factor 1
  • Isonicotinic Acids
  • Ligands
  • Nicotinic Acids