In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1
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 dise...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-07-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2018.00242/full |
| _version_ | 1818441458124849152 |
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| author | Benjamin Kirchweger Jadel M. Kratz Angela Ladurner Ulrike Grienke Thierry Langer Verena M. Dirsch Judith M. Rollinger |
| author_facet | Benjamin Kirchweger Jadel M. Kratz Angela Ladurner Ulrike Grienke Thierry Langer Verena M. Dirsch Judith M. Rollinger |
| author_sort | Benjamin Kirchweger |
| collection | DOAJ |
| description | 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 reaching more than 50% receptor activation at 20 μM with EC50s of 13.53 μM and 13.88 μM, respectively. This activity is comparable to that of the endogenous ligand lithocholic acid (1). Seven further virtual hits showed activity reaching at least 15% receptor activation either at 5 or 20 μM, including new scaffolds from natural and synthetic origin. |
| first_indexed | 2024-12-14T18:28:34Z |
| format | Article |
| id | doaj.art-c0afcca1828e4f18980f618a8eb4299a |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-14T18:28:34Z |
| publishDate | 2018-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-c0afcca1828e4f18980f618a8eb4299a2022-12-21T22:51:52ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462018-07-01610.3389/fchem.2018.00242362421In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1Benjamin Kirchweger0Jadel M. Kratz1Angela Ladurner2Ulrike Grienke3Thierry Langer4Verena M. Dirsch5Judith M. Rollinger6Department of Pharmacognosy, University of Vienna, Vienna, AustriaDepartment of Pharmacognosy, University of Vienna, Vienna, AustriaDepartment of Pharmacognosy, University of Vienna, Vienna, AustriaDepartment of Pharmacognosy, University of Vienna, Vienna, AustriaDepartment of Pharmaceutical Chemistry, University of Vienna, Vienna, AustriaDepartment of Pharmacognosy, University of Vienna, Vienna, AustriaDepartment of Pharmacognosy, University of Vienna, Vienna, AustriaThe 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 reaching more than 50% receptor activation at 20 μM with EC50s of 13.53 μM and 13.88 μM, respectively. This activity is comparable to that of the endogenous ligand lithocholic acid (1). Seven further virtual hits showed activity reaching at least 15% receptor activation either at 5 or 20 μM, including new scaffolds from natural and synthetic origin.https://www.frontiersin.org/article/10.3389/fchem.2018.00242/fullGPBAR1TGR5pharmacophorevirtual screeningnatural producttriterpene |
| spellingShingle | Benjamin Kirchweger Jadel M. Kratz Angela Ladurner Ulrike Grienke Thierry Langer Verena M. Dirsch Judith M. Rollinger In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1 Frontiers in Chemistry GPBAR1 TGR5 pharmacophore virtual screening natural product triterpene |
| title | In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1 |
| title_full | In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1 |
| title_fullStr | In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1 |
| title_full_unstemmed | In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1 |
| title_short | In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1 |
| title_sort | in silico workflow for the discovery of natural products activating the g protein coupled bile acid receptor 1 |
| topic | GPBAR1 TGR5 pharmacophore virtual screening natural product triterpene |
| url | https://www.frontiersin.org/article/10.3389/fchem.2018.00242/full |
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