Small-molecule inhibitors of the m7G-RNA writer METTL1
| Title | Small-molecule inhibitors of the m7G-RNA writer METTL1 |
| Publication Type | Journal Article |
| Year of Publication | 2023 |
| Authors | Nai F., Flores-Espinoza M.P., Invernizzi A., Vargas-Rosales P.A, Bobileva O., Herok M., Caflisch A. |
| Journal | ACS Bio & Med Chem Au |
| Volume | 4 |
| Issue | 2 |
| Pagination | 100-110 |
| Date Published | 2023 Dec 12 |
| Type of Article | Research Article |
| Keywords | docking, 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. |
| URL | https://pubs.acs.org/doi/full/10.1021/acsbiomedchemau.3c00030 |
| DOI | 10.1021/acsbiomedchemau.3c00030 |
| pubindex | 0295 |
| Alternate Journal | ACS Bio. Med. Chem. Au |
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Drug Design