Chemical space virtual screening against hard-to-drug RNA methyltransferases DNMT2 and NSUN6
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Abstract
Targeting RNA methyltransferases with small molecules as inhibitors or tool compounds
is an emerging field of interest in epitranscriptomics and medicinal chemistry. For two challenging
RNA methyltransferases that introduce the 5-methylcytosine (m5C) modification in different tRNAs,
namely DNMT2 and NSUN6, an ultra-large commercially available chemical space was virtually
screened by physicochemical property filtering, molecular docking, and clustering to identify new
ligands for those enzymes. Novel chemotypes binding to DNMT2 and NSUN6 with affinities down to
KD,app = 37 μM and KD,app = 12 μM, respectively, were identified using a microscale thermophoresis
(MST) binding assay. These compounds represent the first molecules with a distinct structure from
the cofactor SAM and have the potential to be developed into activity-based probes for these enzymes.
Additionally, the challenges and strategies of chemical space docking screens with special emphasis
on library focusing and diversification are discussed.
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International Journal of Molecular Sciences, 24, 7, MDPI, Basel, 2023, https://doi.org/10.3390/ijms24076109