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Discovery of a new drug-like series of OGT inhibitors by virtual screening
ID
Loi, Elena Maria
(
Author
),
ID
Tomašič, Tihomir
(
Author
),
ID
Balsollier, Cyril
(
Author
),
ID
van Eekelen, Kevin
(
Author
),
ID
Weiss, Matjaž
(
Author
),
ID
Gobec, Martina
(
Author
),
ID
Alteen, Matthew G
(
Author
),
ID
Vocadlo, David J.
(
Author
),
ID
Pieters, Roland J.
(
Author
),
ID
Anderluh, Marko
(
Author
)
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MD5: 39D01ECF24B3BB2C66A98BE71134677D
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https://www.mdpi.com/1420-3049/27/6/1996
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Abstract
O-GlcNAcylation is an essential post-translational modification installed by the enzyme O-β-N-acetyl-d-glucosaminyl transferase (OGT). Modulating this enzyme would be extremely valuable to better understand its role in the development of serious human pathologies, such as diabetes and cancer. However, the limited availability of potent and selective inhibitors hinders the validation of this potential therapeutic target. To explore new chemotypes that target the active site of OGT, we performed virtual screening of a large library of commercially available compounds with drug-like properties. We purchased samples of the most promising virtual hits and used enzyme assays to identify authentic leads. Structure-activity relationships of the best identified OGT inhibitor were explored by generating a small library of derivatives. Our best hit displays a novel uridine mimetic scaffold and inhibited the recombinant enzyme with an IC50 value of 7 µM. The current hit represents an excellent starting point for designing and developing a new set of OGT inhibitors that may prove useful for exploring the biology of OGT.
Language:
English
Keywords:
O-GlcNAc transferase
,
OGT inhibitors
,
virtual screening
,
pharmaceutical chemistry
Work type:
Article
Typology:
1.01 - Original Scientific Article
Organization:
FFA - Faculty of Pharmacy
Year:
2022
Number of pages:
21 str.
Numbering:
Vol. 27, iss. 6, art 1996
PID:
20.500.12556/RUL-137516-b0f223a7-0e4a-1d65-94f4-52e297b46d04
UDC:
615.4:54
ISSN on article:
1420-3049
DOI:
10.3390/molecules27061996
COBISS.SI-ID:
101699843
Publication date in RUL:
20.06.2022
Views:
1238
Downloads:
123
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Record is a part of a journal
Title:
Molecules
Shortened title:
Molecules
Publisher:
MDPI
ISSN:
1420-3049
COBISS.SI-ID:
18462981
Licences
License:
CC BY 4.0, Creative Commons Attribution 4.0 International
Link:
http://creativecommons.org/licenses/by/4.0/
Description:
This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Licensing start date:
19.03.2022
Secondary language
Language:
Slovenian
Keywords:
O-GlcNAc transferaza
,
zaviralci OGT
,
virtualno rešetanje
,
farmacevtska kemija
Projects
Funder:
EC - European Commission
Funding programme:
H2020
Project number:
765581
Name:
Multidisciplinary European Joint Doctorate in the Design and Development of Glyco Drugs
Acronym:
PhD4GlycoDrug
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0208
Name:
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin
Funder:
Other - Other funder or multiple funders
Funding programme:
COST actions
Project number:
CA18103
Acronym:
Innogly
Funder:
Other - Other funder or multiple funders
Funding programme:
COST actions
Project number:
CA18132
Acronym:
GLYCONanoPROBES
Funder:
Other - Other funder or multiple funders
Funding programme:
Canadian Institutes of Health Research
Project number:
PJT-148732
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