Virtual screening and biological characterization of novel histone arginine methyltransferase PRMT1 inhibitors

ChemMedChem. 2009 Jan;4(1):69-77. doi: 10.1002/cmdc.200800301.


Lysine and arginine methyltransferases participate in the posttranslational modification of histones and regulate key cellular functions. Protein arginine methyltransferase 1 (PRMT1) has been identified as an essential component of mixed lineage leukemia (MLL) oncogenic complexes, revealing its potential as a novel therapeutic target in human cancer. The first potent arginine methyltransferase inhibitors were recently discovered by random- and target-based screening approaches. Herein we report virtual and biological screening for novel inhibitors of PRMT1. Structure-based virtual screening (VS) of the Chembridge database composed of 328 000 molecules was performed with a combination of ligand- and target-based in silico approaches. Nine inhibitors were identified from the top-scored docking solutions; these were experimentally tested using human PRMT1 and an antibody-based assay with a time-resolved fluorescence readout. Among several aromatic amines, an aliphatic amine and an amide were also found to be active in the micromolar range.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Databases, Factual
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Protein Structure, Tertiary
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors
  • Protein-Arginine N-Methyltransferases / chemistry*
  • Rats


  • Enzyme Inhibitors
  • Protein-Arginine N-Methyltransferases