Identification and development of a small molecule probe for GNMT

National Center For Advancing Translational Sciences

Investigators

Abstract

The NCATS project team developed six unique primary assays for the methyltransferases (MTase) NNMT, PNMT, COMT, HNMT, GNMT, and GAMT, and also developed a counter-assay using the Methyltransferase Glo kit from Promega. To date the team has screened 12,000 compounds from Genesis MiniMe, LOPAC, and the Epigenetic Collection to begin building the activity profiles for each MTase. Virtual docking simulations and protein structure comparison efforts were launched to inform hypotheses about compounds which are pan inhibitors of the MTases (e.g., what contacts between compound and amino acid are conserved among these MTases?) and which are selective to individual MTases (e.g., what chemical features are important for inhibiting NNMT vs PNMT or GAMT?). Current work is focused on high-throughput screening and subsequent medicinal chemistry to identify and characterize GNMT-specific inhibitors as chemical probes.