Small-Molecule Inhibitors of the m7G-RNA Writer METTL1

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 40–300 μM. Two adenine derivatives identified by docking have v...

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Bibliographic Details
Published in:ACS bio & med chem au 2024-04, Vol.4 (2), p.100-110
Main Authors: Nai, Francesco, Flores Espinoza, Maria Paula, Invernizzi, Annalisa, Vargas-Rosales, Pablo Andrés, Bobileva, Olga, Herok, Marcin, Caflisch, Amedeo
Format: Article
Language:English
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Summary: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 40–300 μM. 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-adenosyl methionine 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 1.85 Å.
ISSN:2694-2437
2694-2437
DOI:10.1021/acsbiomedchemau.3c00030