In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1

Frontiers in Chemistry
Benjamin KirchwegerJudith M Rollinger

Abstract

The G protein-coupled bile acid receptor (GPBAR1) has been recognized as a promising new target for the treatment of diverse diseases, including obesity, type 2 diabetes, fatty liver disease and atherosclerosis. The identification of novel and potent GPBAR1 agonists is highly relevant, as these diseases are on the rise and pharmacological unmet therapeutic needs are pervasive. Therefore, the aim of this study was to develop a proficient workflow for the in silico prediction of GPBAR1 activating compounds, primarily from natural sources. A protocol was set up, starting with a comprehensive collection of structural information of known ligands. This information was used to generate ligand-based pharmacophore models in LigandScout 4.08 Advanced. After theoretical validation, the two most promising models, namely BAMS22 and TTM8, were employed as queries for the virtual screening of natural product and synthetic small molecule databases. Virtual hits were progressed to shape matching experiments and physicochemical clustering. Out of 33 diverse virtual hits subjected to experimental testing using a reporter gene-based assay, two natural products, farnesiferol B (27) and microlobidene (28), were confirmed as GPBAR1 activators reachi...Continue Reading

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Citations

Oct 9, 2018·Scandinavian Journal of Gastroenterology·Norman B Javitt
Dec 18, 2019·International Journal of Molecular Sciences·Lu ZhangZhibo Gai
Jul 30, 2020·Molecular Informatics·Ya Chen, Johannes Kirchmair
Nov 21, 2020·Biomolecules·José L Medina-Franco, Fernanda I Saldívar-González

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Methods Mentioned

BETA
NMR

Software Mentioned

FAF
LigandScout
GraphPad Prism
OpenEye ROCS
ComboScore
chemGPS
DUDE
SIMCA
ChEMBL
ROCS

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