Autoren:	Zimmermann, Robert A. Fischer, Tim R. Schwickert, Marvin Nidoieva, Zarina Schirmeister, Tanja Kersten, Christian
Titel:	Chemical space virtual screening against hard-to-drug RNA methyltransferases DNMT2 and NSUN6
Online-Publikationsdatum:	18-Apr-2023
Erscheinungsdatum:	2023
Sprache des Dokuments:	Englisch
Zusammenfassung/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-Sachgruppe:	540 Chemie 540 Chemistry and allied sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 09 Chemie, Pharmazie u. Geowissensch.
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-9019
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Weitere Angaben zur Dokumentart:	Scientific article
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	International Journal of Molecular Sciences 24 7
Seitenzahl oder Artikelnummer:	6109
Verlag:	MDPI
Verlagsort:	Basel
Erscheinungsdatum:	2023
ISSN:	1422-0067
DOI der Originalveröffentlichung:	10.3390/ijms24076109
Enthalten in den Sammlungen:	DFG-491381577-G