Discovery of a New Drug-like Series of OGT Inhibitors by Virtual Screening
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
|---|---|
| Enthalten in: |
Molecules (Basel, Switzerland) - 27(2022), 6 vom: 19. März |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Loi, Elena M [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
EC 2.4.1.- |
|---|
| Anmerkungen: |
Date Completed 30.03.2022 Date Revised 01.04.2022 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.3390/molecules27061996 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM338656014 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM338656014 | ||
| 003 | DE-627 | ||
| 005 | 20231226001148.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/molecules27061996 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1128.xml |
| 035 | |a (DE-627)NLM338656014 | ||
| 035 | |a (NLM)35335358 | ||
| 035 | |a (PII)1996 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Loi, Elena M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of a New Drug-like Series of OGT Inhibitors by Virtual Screening |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 30.03.2022 | ||
| 500 | |a Date Revised 01.04.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a O-GlcNAc transferase | |
| 650 | 4 | |a OGT inhibitors | |
| 650 | 4 | |a virtual screening | |
| 650 | 7 | |a N-Acetylglucosaminyltransferases |2 NLM | |
| 650 | 7 | |a EC 2.4.1.- |2 NLM | |
| 700 | 1 | |a Tomašič, Tihomir |e verfasserin |4 aut | |
| 700 | 1 | |a Balsollier, Cyril |e verfasserin |4 aut | |
| 700 | 1 | |a van Eekelen, Kevin |e verfasserin |4 aut | |
| 700 | 1 | |a Weiss, Matjaž |e verfasserin |4 aut | |
| 700 | 1 | |a Gobec, Martina |e verfasserin |4 aut | |
| 700 | 1 | |a Alteen, Matthew G |e verfasserin |4 aut | |
| 700 | 1 | |a Vocadlo, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Pieters, Roland J |e verfasserin |4 aut | |
| 700 | 1 | |a Anderluh, Marko |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecules (Basel, Switzerland) |d 2004 |g 27(2022), 6 vom: 19. März |w (DE-627)NLM172073448 |x 1420-3049 |7 nnns |
| 773 | 1 | 8 | |g volume:27 |g year:2022 |g number:6 |g day:19 |g month:03 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/molecules27061996 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 27 |j 2022 |e 6 |b 19 |c 03 | ||