Molecular Field Analysis and 3D-Quantitative Structure−Activity Relationship Study (MFA 3D-QSAR) Unveil Novel Features of Bile Acid Recognition at TGR5

Abstract

Bile acids regulate nongenomic actions through the activation of TGR5, a membrane receptor that is G protein-coupled to the induction of adenylate cyclase. In this work, a training set of 43 bile acid derivatives is used to develop a molecular interaction field analysis (MFA) and a 3D-quantitative structure-activity relationship study (3D-QSAR) of TGR5 agonists. The predictive ability of the resulting model is evaluated using an external set of compounds with known TGR5 activity, and six bile acid derivatives whose unknown TGR5 activity is herein assessed with in vitro luciferase assay of cAMP formation. The results show a good predictive model and indicate a statistically relevant degree of correlation between the TGR5 activity and the molecular interaction fields produced by discrete positions of the bile acid scaffold. This information is instrumental to extend on a quantitative basis the current structure-activity relationships of bile acids as TGR5 modulators and will be fruitful to design new potent and selective agonists of the receptor.

Discovery of 6α-Ethyl-23(S)-methylcholic Acid (S-EMCA, INT-777) as a Potent and Selective Agonist for the TGR5 Receptor, a Novel Target for Diabesity

“…In the resulting derivative 7, the FXR activity was remarkably decreased (FXR-EC 50 = 11.80 μM) and the TGR5 efficacy boosted to nanomolar concentration (TGR5-EC 50 =0.095 μM). 19 Further conclusions on the structure-activity relationships (SAR) profile of BA-derived TGR5 agonists were also drawn by the results of our screening. 6,19 As a continuation to this work and to find a suitable candidate for TGR5 clinical studies, we directed our attention to the optimization of 7 in search for a compound endowed not only with analogous properties of efficacy and selectivity but also with improved pharmacokinetic properties and a more favorable metabolic profile.…”

“…As a result, we discovered that the incorporation of a methyl moiety with the preference of the S over the R chiral configuration at the C 23 position of the CDCA side chain (3) afforded selective, albeit not very potent, TGR5 agonist properties (6, TGR5-EC 50 = 3.58 μM, FXR-EC 50 > 100 μM). 19 When this additional chemical feature was next introduced in 6-ECDCA (5), we were pleasantly surprised to discover a remarkable reversal of the activity profile. In the resulting derivative 7, the FXR activity was remarkably decreased (FXR-EC 50 = 11.80 μM) and the TGR5 efficacy boosted to nanomolar concentration (TGR5-EC 50 =0.095 μM).…”

Patented TGR5 modulators: a review (2006 – present)

“…While the first synthesis of the CDCA and LCA enantiomers allowed to assess the specificity of BA interaction at TGR5 [27], screening of semisynthetic BA libraries and rational modifications of the BA scaffold proved successful to disclose new TGR5 ligands endowed with different potency and selectivity index, as well as with diverse physicochemical and ADMET (absorption, distribution, metabolism, elimination, toxicology) profile [21,[28][29][30][31][32][33][34][35][36].…”

Chapter 10. TGR5 Agonists in Development

“…79 While being able to explain much of the variance of the 43 training set BAs and satisfactorily predicting the 70% rate of an external test set of 20 BAs, the 3D-QSAR model disclosed essential interactions implicated in the recognition of the TGR5-binding site that were in agreement with the structure-activity relationship scheme of BAs ( Figure 10.12).…”