Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization

Journal of Cheminformatics
Obdulia RabalJulen Oyarzabal

Abstract

Epigenetic therapies are being investigated for the treatment of cancer, cognitive disorders, metabolic alterations and autoinmune diseases. Among the different epigenetic target families, protein lysine methyltransferases (PKMTs), are especially interesting because it is believed that their inhibition may be highly specific at the functional level. Despite its relevance, there are currently known inhibitors against only 10 out of the 50 SET-domain containing members of the PKMT family. Accordingly, the identification of chemical probes for the validation of the therapeutic impact of epigenetic modulation is key. Moreover, little is known about the mechanisms that dictate their substrate specificity and ligand selectivity. Consequently, it is desirable to explore novel methods to characterize the pharmacological similarity of PKMTs, going beyond classical phylogenetic relationships. Such characterization would enable the prediction of ligand off-target effects caused by lack of ligand selectivity and the repurposing of known compounds against alternative targets. This is particularly relevant in the case of orphan targets with unreported inhibitors. Here, we first perform a systematic study of binding modes of cofactor and subs...Continue Reading

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Citations

Feb 16, 2020·Journal of Computer-aided Molecular Design·Edgar López-LópezJosé L Medina-Franco
Mar 3, 2021·Nature Chemical Biology·Tony NgoNicola J Smith

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Methods Mentioned

BETA
X-ray

Software Mentioned

PKMT
ICM
CoINPocket
iTOL
SVL script
ClustalW
GPCR
BaSiLico
ChEMBL
FCFP

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