title: Virtual screening and biological characterization of novel histone arginine methyltransferase PRMT1 inhibitors.
abstract: 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.
authors.affiliation: Universität Halle-Wittenberg, Department of Pharmaceutical Chemistry, Wolfgang-Langenbeckstrasse 4, 06120 Halle/Saale, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Heinke
authors.forename: Astrid
authors.initials: A
authors.lastname: Spannhoff
authors.forename: Rene
authors.initials: R
authors.lastname: Meier
authors.forename: Patrick
authors.initials: P
authors.lastname: Trojer
authors.forename: Ingo
authors.initials: I
authors.lastname: Bauer
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D011484:Protein-Arginine N-Methyltransferases