Author
Keywords
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.

Year of Publication
2023
Journal
ACS Bio & Med Chem Au
Volume
4
Issue
2
Number of Pages
100-110
Date Published
2023 Dec 12
Type of Article
Research Article
URL
https://pubs.acs.org/doi/full/10.1021/acsbiomedchemau.3c00030
DOI
10.1021/acsbiomedchemau.3c00030
Alternate Journal
ACS Bio. Med. Chem. Au
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