Benjamin Kirchweger, Jadel M. Kratz, Angela Ladurner, Ulrike Grienke, Thierry Langer, Verena M. Dirsch, Judith 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 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.
Pharmacology, Toxicology and Pharmaceutical Science
2
6%
Unspecified
2
6%
Other
5
16%
Unknown
12
38%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 02 July 2018.
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#18,641,800
of 23,094,276 outputs
Outputs from Frontiers in Chemistry
#2,238
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Outputs of similar age
#253,185
of 327,941 outputs
Outputs of similar age from Frontiers in Chemistry
#74
of 179 outputs
Altmetric has tracked 23,094,276 research outputs across all sources so far. This one is in the 11th percentile – i.e., 11% of other outputs scored the same or lower than it.
So far Altmetric has tracked 6,038 research outputs from this source. They receive a mean Attention Score of 2.1. This one has gotten more attention than average, scoring higher than 51% of its peers.
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