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

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

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Universit├Ąt Halle-Wittenberg, Department of Pharmaceutical Chemistry, Wolfgang-Langenbeckstrasse 4, 06120 Halle/Saale, Germany.


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.

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