The RNA methylase METTL3 catalyzes the transfer of a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to the N6 atom of adenine. We have screened a library of 4000 analogues and derivatives of the adenosine moiety of SAM by high-throughput docking into METTL3. Two series of adenine derivatives were identified in silico, and the binding mode of six of the predicted inhibitors was validated by protein crystallography. Two compounds, one for each series, show good ligand efficiency. We propose a route for their further development into potent and selective inhibitors of METTL3.
BT - ChemMedChem C1 - 0253 DA - 2020 Mar 11 DO - 10.1002/cmdc.202000011 IS - 9 J2 - ChemMedChem LA - eng M3 - Research Article N2 -The RNA methylase METTL3 catalyzes the transfer of a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to the N6 atom of adenine. We have screened a library of 4000 analogues and derivatives of the adenosine moiety of SAM by high-throughput docking into METTL3. Two series of adenine derivatives were identified in silico, and the binding mode of six of the predicted inhibitors was validated by protein crystallography. Two compounds, one for each series, show good ligand efficiency. We propose a route for their further development into potent and selective inhibitors of METTL3.
PY - 2020 SP - 744 EP - 748 T2 - ChemMedChem TI - Small-molecule inhibitors of METTL3, the major human epitranscriptomic writer VL - 15 SN - 1860-7187 ER -