Small molecule inhibitors of histone arginine methyltransferases: homology modeling, molecular docking, binding mode analysis, and biological evaluations

J Med Chem. 2007 Mar 22;50(6):1241-53. doi: 10.1021/jm061213n. Epub 2007 Feb 27.

Abstract

The screening of the inhibition capabilities of dye-like small molecules from a focused library against both human PRMT1 and Aspergillus nidulans RmtA is reported as well as molecular modeling studies (homology modeling, molecular docking, and 3-D QSAR) of the catalytic domain of the PRMT1 fungal homologue RmtA. The good correlation between computational and biological results makes RmtA a reliable tool for screening arginine methyltransferase inhibitors. In addition, the binding mode analyses of tested derivatives reveal the crucial role of two regions, the pocket formed by Ile12, His13, Met16, and Thr49 and the SAM cisteinic binding site subsite. These regions should be taken into account in the design of novel PRMT inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Aspergillus nidulans / enzymology
  • Benzoates / chemical synthesis
  • Benzoates / chemistry
  • Binding Sites
  • Catalytic Domain
  • Databases, Protein
  • Humans
  • Ligands
  • Models, Molecular*
  • Molecular Sequence Data
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Protein Conformation
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Protein-Arginine N-Methyltransferases / chemistry*
  • Quantitative Structure-Activity Relationship
  • Rats
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / chemistry*
  • Sequence Homology, Amino Acid
  • Sulfonic Acids / chemical synthesis*
  • Sulfonic Acids / chemistry
  • Triazines / chemical synthesis*
  • Triazines / chemistry
  • Xanthenes / chemical synthesis*
  • Xanthenes / chemistry

Substances

  • Benzoates
  • Ligands
  • Naphthalenes
  • Repressor Proteins
  • Sulfonic Acids
  • Triazines
  • Xanthenes
  • PRMT1 protein, human
  • Protein-Arginine N-Methyltransferases