Authors:	Zimmermann, Robert A. Fischer, Tim R. Schwickert, Marvin Nidoieva, Zarina Schirmeister, Tanja Kersten, Christian
Title:	Chemical space virtual screening against hard-to-drug RNA methyltransferases DNMT2 and NSUN6
Online publication date:	18-Apr-2023
Year of first publication:	2023
Language:	english
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.
DDC:	540 Chemie 540 Chemistry and allied sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 09 Chemie, Pharmazie u. Geowissensch.
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-9019
Version:	Published version
Publication type:	Zeitschriftenaufsatz
Document type specification:	Scientific article
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	International Journal of Molecular Sciences 24 7
Pages or article number:	6109
Publisher:	MDPI
Publisher place:	Basel
Issue date:	2023
ISSN:	1422-0067
Publisher DOI:	10.3390/ijms24076109
Appears in collections:	DFG-491381577-G