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Virtual Screening and Biological Characterization of Novel Histone Arginine Methyltransferase PRMT1 Inhibitors
Author(s) -
Heinke Ralf,
Spannhoff Astrid,
Meier Rene,
Trojer Patrick,
Bauer Ingo,
Jung Manfred,
Sippl Wolfgang
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800301
Subject(s) - virtual screening , methyltransferase , arginine , protein arginine methyltransferase 5 , in silico , histone methyltransferase , histone , chemistry , docking (animal) , methylation , computational biology , small molecule , biochemistry , lysine , biology , amino acid , drug discovery , medicine , dna , nursing , gene
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.