Chemical Space Virtual Screening against Hard-to-Drug RNA Methyltransferases DNMT2 and NSUN6
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Robert A Zimmermann
- Tim R Fischer
- Marvin Schwickert
- Zarina Nidoieva
- Tanja Schirmeister
- Christian Kersten
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000970331900001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.3390/ijms24076109
- eISSN
- 1422-0067
- Externe Identifier
- Clarivate Analytics Document Solution ID: D7EW9
- PubMed Identifier: 37047081
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
- Schlüsselwörter
- RNA methyltransferases
- DNMT2
- NSUN6
- virtual screening
- ultra-large molecular libraries
- molecular docking
- chemical spaces
- Artikelnummer
- ARTN 6109
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Titel
- Chemical Space Virtual Screening against Hard-to-Drug RNA Methyltransferases DNMT2 and NSUN6
- Sub types
- Article
- Ausgabe der Zeitschrift
- 24
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Abstract
- <jats:p>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.</jats:p>
- Autoren
- Robert A Zimmermann
- Tim R Fischer
- Marvin Schwickert
- Zarina Nidoieva
- Tanja Schirmeister
- Christian Kersten
- DOI
- 10.3390/ijms24076109
- eISSN
- 1422-0067
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- International Journal of Molecular Sciences
- Sprache
- en
- Online publication date
- 2023
- Paginierung
- 6109 - 6109
- Status
- Published online
- Herausgeber
- MDPI AG
- Herausgeber URL
- http://dx.doi.org/10.3390/ijms24076109
- Datum der Datenerfassung
- 2023
- Titel
- Chemical Space Virtual Screening against Hard-to-Drug RNA Methyltransferases DNMT2 and NSUN6
- Ausgabe der Zeitschrift
- 24
Datenquelle: Crossref
- 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 (m<sup>5</sup>C) 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 K<sub>D,app</sub> = 37 µM and K<sub>D,app</sub> = 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.
- Addresses
- Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University, Staudingerweg 5, 55128 Mainz, Germany.
- Autoren
- Robert A Zimmermann
- Tim R Fischer
- Marvin Schwickert
- Zarina Nidoieva
- Tanja Schirmeister
- Christian Kersten
- DOI
- 10.3390/ijms24076109
- eISSN
- 1422-0067
- Externe Identifier
- PubMed Identifier: 37047081
- PubMed Central ID: PMC10094593
- Funding acknowledgements
- Federal Ministry of Education and Research: BMBF/ 01ED1804
- DFG: projects A01
- Volkswagenstiftung: Soforthilfe Ukraine
- Bundesministerium für Bildung und Forschung: BMBF/01ED1804
- Volkswagen Stiftung:
- Deutsche Forschungsgemeinschaft: Transregio Collaborative Research Center TRR 319 (RMaP, RNA Modification and Processing, project A01)
- Open access
- true
- ISSN
- 1422-0067
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- International journal of molecular sciences
- Schlüsselwörter
- Methyltransferases
- tRNA Methyltransferases
- RNA
- RNA, Transfer
- Molecular Docking Simulation
- DNA (Cytosine-5-)-Methyltransferases
- Sprache
- eng
- Medium
- Electronic
- Online publication date
- 2023
- Open access status
- Open Access
- Paginierung
- 6109
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2023
- Titel
- Chemical Space Virtual Screening against Hard-to-Drug RNA Methyltransferases DNMT2 and NSUN6.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 24
Files
https://www.mdpi.com/1422-0067/24/7/6109/pdf?version=1679629767 https://europepmc.org/articles/PMC10094593?pdf=render
Datenquelle: Europe PubMed Central
- 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.
- Date of acceptance
- 2023
- Autoren
- Robert A Zimmermann
- Tim R Fischer
- Marvin Schwickert
- Zarina Nidoieva
- Tanja Schirmeister
- Christian Kersten
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/37047081
- DOI
- 10.3390/ijms24076109
- eISSN
- 1422-0067
- Externe Identifier
- PubMed Central ID: PMC10094593
- Funding acknowledgements
- Deutsche Forschungsgemeinschaft: Transregio Collaborative Research Center TRR 319 (RMaP, RNA Modification and Processing, project A01)
- Volkswagenstiftung: Soforthilfe Ukraine
- Federal Ministry of Education and Research: BMBF/ 01ED1804
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- Int J Mol Sci
- Schlüsselwörter
- DNMT2
- NSUN6
- RNA methyltransferases
- chemical spaces
- molecular docking
- ultra-large molecular libraries
- virtual screening
- Methyltransferases
- Molecular Docking Simulation
- RNA
- RNA, Transfer
- DNA (Cytosine-5-)-Methyltransferases
- tRNA Methyltransferases
- Sprache
- eng
- Country
- Switzerland
- PII
- ijms24076109
- Datum der Veröffentlichung
- 2023
- Status
- Published online
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2023
- Titel
- Chemical Space Virtual Screening against Hard-to-Drug RNA Methyltransferases DNMT2 and NSUN6.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 24
Datenquelle: PubMed
- Author's licence
- CC-BY
- Autoren
- Robert A Zimmermann
- Tim R Fischer
- Marvin Schwickert
- Zarina Nidoieva
- Tanja Schirmeister
- Christian Kersten
- Hosting institution
- Universitätsbibliothek Mainz
- Sammlungen
- DFG-491381577-G
- Resource version
- Published version
- DOI
- 10.3390/ijms24076109
- File(s) embargoed
- false
- Open access
- true
- ISSN
- 1422-0067
- Ausgabe der Veröffentlichung
- 7
- Zeitschrift
- International Journal of Molecular Sciences
- Schlüsselwörter
- 540 Chemie
- 540 Chemistry and allied sciences
- Sprache
- eng
- Open access status
- Open Access
- Paginierung
- 6109
- Datum der Veröffentlichung
- 2023
- Public URL
- https://openscience.ub.uni-mainz.de/handle/20.500.12030/9036
- Herausgeber
- MDPI
- Datum der Datenerfassung
- 2023
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2023
- Zugang
- Public
- Titel
- Chemical space virtual screening against hard-to-drug RNA methyltransferases DNMT2 and NSUN6
- Ausgabe der Zeitschrift
- 24
Files
chemical_space_virtual_screen-20230418075719562.pdf
Datenquelle: OPENSCIENCE.UB
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- Eigentum von