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.
BT - ACS Bio & Med Chem Au C1 - 0295 DA - 2023 Dec 12 DO - 10.1021/acsbiomedchemau.3c00030 IS - 2 J2 - ACS Bio. Med. Chem. Au LA - eng M3 - Research Article N2 -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.
PY - 2023 SP - 100 EP - 110 T2 - ACS Bio & Med Chem Au TI - Small-molecule inhibitors of the m7G-RNA writer METTL1 UR - https://pubs.acs.org/doi/full/10.1021/acsbiomedchemau.3c00030 VL - 4 ER -