Small-Molecule Inhibitors of the m7G-RNA Writer METTL1

TitleSmall-Molecule Inhibitors of the m7G-RNA Writer METTL1
Publication TypeJournal Article
Year of Publication2023
AuthorsNai F., Flores-Espinoza M.P., Invernizzi A., Vargas-Rosales P.A, Bobileva O., Herok M., Caflisch A.
JournalACS Bio & Med Chem Au
VolumeX
Date Published2023 Dec 12
Type of ArticleResearch Article
Keywordsdocking, Drug Discovery, enzymatic assay, epitranscriptomics, m7G writer, MD simulation
Abstract

We discovered the first inhibitors of the m7G-RNA writer METTL1 by high-throughput docking and an enzymatic assay based on luminescence. Eleven compounds, which belong to three different chemotypes, show inhibitory activity in the range 40-300uM Two adenine derivatives identified by docking have very favorable ligand efficiency of 0.34 and 0.31 kcal/mol per non-hydrogen atom, respectively. Molecular dynamics simulations provide evidence that the inhibitors compete with the binding of the cosubstrate S-adenosylmethionine to METTL1. We also present a soakable crystal form that was used to determine the structure of the complex of METTL1 with sinefungin at a resolution of 1.85A.

URLhttps://pubs.acs.org/doi/full/10.1021/acsbiomedchemau.3c00030
DOI10.1021/acsbiomedchemau.3c00030
pubindex

0295

Alternate JournalACS Bio. Med. Chem. Au
Highlight Role: 
Drug Design