Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism.

Francesco Saverio Di Leva,Stefano Fiorucci,Carmen Festa,Barbara Renga,Angela Zampella,Ettore Novellino,Valentina Sepe,Vittorio Limongelli

doi:10.1038/srep16605

Francesco Saverio Di Leva, Stefano Fiorucci + Show 6 more

Open Access

https://doi.org/10.1038/srep16605

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Abstract

Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

Highlights

Adipose tissue, skeletal muscle cells and macrophages/monocytes
A marked selectivity toward GPBAR1 over farnesoid X receptor (FXR) has been achieved through the methylation at C-23 position on the Bile acids (BAs) side chain (INT-777)[18], and by stereochemical modification on ring B generating EUCDCOH, which is the first example of UDCA derivative substituted at C-6 with a β -oriented ethyl group[19]
Hydrogenation (H2, Pd/C) afforded methyl 3β -amino lithocholic acid (LCA) 7 that was used as starting material for the preparation of 6 and 8 by methyl ester hydrolysis and methyl ester reduction, respectively (Fig. 4)

Summary

Introduction

Adipose tissue, skeletal muscle cells and macrophages/monocytes. Among the most potent natural agonists of GPBAR1 is the tauro-conjugated form of LCA, tauro-lithocolic acid (TLCA, 1)[7,8]. Independently from the functional group at C-24 on the side chain, the removal of the 3α -OH from the CDCA scaffold provides potent and selective FXR agonists[19] In spite of these examples, a comprehensive understanding of the effects of BAs modifications on the activity and selectivity towards GPBAR1 and FXR is possible only if the binding mode of these compounds to the two receptors is elucidated. This is difficult because of the lack of the tridimensional structure of human GPBAR1 (hGPBAR1). Our findings open new routes to design selective GPBAR1 ligands and towards a rational modulation of BA receptors activity

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Conclusion