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On the relationship of anthranilic derivatives structure and the FXR (Farnesoid X receptor) agonist activity

: Kronenberger, T.; Windshügel, B.; Wrenger, C.; Honorio, K.M.; Maltarollo, V.G.


Journal of biomolecular structure & dynamics 36 (2018), Nr.16, S.4378-4391
ISSN: 0739-1102
ISSN: 1538-0254
Fraunhofer IME ()

Farnesoid X receptor (FXR) is a nuclear receptor related to lipid and glucose homeostasis and is considered an important molecular target to treatment of metabolic diseases as diabetes, dyslipidemia, and liver cancer. Nowadays, there are several FXR agonists reported in the literature and some of it in clinical trials for liver disorders. Herein, a compound series was employed to generate QSAR models to better understand the structural basis for FXR activation by anthranilic acid derivatives (AADs). Furthermore, here we evaluate the inclusion of the standard deviation (SD) of EC50 values in QSAR models quality. Comparison between the use of experimental variance plus average values in model construction with the standard method of model generation that considers only the average values was performed. 2D and 3D QSAR models based on the AAD data set including SD values showed similar molecular interpretation maps and quality (Q2 LOO, Q2 (F2), and Q2 (F3)), when compared to models based only on average values. SD-based models revealed more accurate predictions for the set of test compounds, with lower mean absolute error indices as well as more residuals near zero. Additionally, the visual interpretation of different QSAR approaches agrees with experimental data, highlighting key elements for understanding the biological activity of AADs. The approach using standard deviation values may offer new possibilities for generating more accurate QSAR models based on available experimental data.