The discovery of a new nonbile acid modulator of Takeda G protein-coupled receptor 5: An integrated computational approach
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F25%3A10505541" target="_blank" >RIV/00216208:11160/25:10505541 - isvavai.cz</a>
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=aepW0PwpHd" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=aepW0PwpHd</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/ardp.202400423" target="_blank" >10.1002/ardp.202400423</a>
Alternative languages
Result language
angličtina
Original language name
The discovery of a new nonbile acid modulator of Takeda G protein-coupled receptor 5: An integrated computational approach
Original language description
The Takeda G protein-coupled receptor 5 (TGR5), also known as GPBAR1 (G protein-coupled bile acid receptor), is a membrane-type bile acid receptor that regulates blood glucose levels and energy expenditure. These essential functions make TGR5 a promising target for the treatment of type 2 diabetes and metabolic disorders. Currently, most research on developing TGR5 agonists focuses on modifying the structure of bile acids, which are the endogenous ligands of TGR5. However, TGR5 agonists with nonsteroidal structures have not been widely explored. This study aimed at discovering new TGR5 agonists using bile acid derivatives as a basis for a computational approach. We applied a combination of pharmacophore-based, molecular docking, and molecular dynamic (MD) simulation to identify potential compounds as new TGR5 agonists. Through pharmacophore screening and molecular docking, we identified 41 candidate compounds. From these, five candidates were selected based on criteria including pharmacophore features, a docking score of less than 9.2 kcal/mol, and similarity in essential interaction patterns with a reference ligand. Biological assays of the five hits confirmed that Hit-3 activates TGR5 similarly to the bile acid control. This was supported by MD simulation results, which indicated that a hydrogen bond interaction with Tyr240 is involved in TGR5 activation. Hit-3 (CSC089939231) represents a new nonsteroidal lead that can be further optimized to design potent TGR5 agonists.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
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Continuities
S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Archiv der Pharmazie
ISSN
0365-6233
e-ISSN
1521-4184
Volume of the periodical
358
Issue of the periodical within the volume
1
Country of publishing house
DE - GERMANY
Number of pages
13
Pages from-to
e2400423
UT code for WoS article
001395148400001
EID of the result in the Scopus database
2-s2.0-85214661840