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Small‐Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer
Author(s) -
Bedi Rajiv K.,
Huang Danzhi,
Eberle Stefanie A.,
Wiedmer Lars,
Śledź Pawel,
Caflisch Amedeo
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000011
Subject(s) - moiety , docking (animal) , stereochemistry , in silico , small molecule , ligand efficiency , chemistry , ligand (biochemistry) , cofactor , adenosine , molecule , biochemistry , enzyme , receptor , gene , medicine , nursing , organic chemistry
The RNA methylase METTL3 catalyzes the transfer of a methyl group from the cofactor S‐adenosyl‐L‐methionine (SAM) to the N 6 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.