Epoxide functionalization on cholane side chains in the identification of G-protein coupled bile acid receptor (GPBAR1) selective agonists

Marino, Simona De; Carino, Adriana; Masullo, Dario; Finamore, Claudia; Sepe, Valentina; Marchianò, Silvia; Leva, Francesco Saverio Di; Limongelli, Vittorio; Fiorucci, Stefano; Zampella, Angela

doi:10.1039/c7ra04922f

Cited by 4 publications

(7 citation statements)

References 37 publications

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“…In order to elucidate the binding mode of the newly synthesized derivatives to GPBAR1, molecular modeling studies were carried out on the most promising derivative of the series, 10 . First, molecular docking calculations were performed on 10 in the 3D homology model of GPBAR1, which we originally built in 2014 24 and validated in the following years with a number of successful drug design studies 33,34,46,47 . Among the binding modes predicted by docking, only two poses interact with Glu169 of GPBAR1 (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Transactivation assay on HEK-293T cells was performed to investigate GPBAR1 activation, using compound 1 – 14 and TLCA as positive control at 10 µM, as previously reported 47 . EC 50 of compounds 9 and 10 was evaluated treating HEK-293T cells transfected with increasing concentrations of two compounds (range from 1 to 50 µM).…”

Section: Methodsmentioning

confidence: 99%

“…Evaluation of proglucagon mRNA expression was performed in RT-PCR on GLUTag cells (1 × 10 6 cells/well in a 6 well plate) as previously reported 34,47 . The relative mRNA expression was calculated and expressed as 2 −(ΔΔCt) .…”

Section: Methodsmentioning

confidence: 99%

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Discovery of ((1,2,4-oxadiazol-5-yl)pyrrolidin-3-yl)ureidyl derivatives as selective non-steroidal agonists of the G-protein coupled bile acid receptor-1

Leva

Festa

Carino³

et al. 2019

Sci Rep

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The G-protein bile acid receptor 1 (GPBAR1) has emerged in the last decade as prominent target for the treatment of metabolic and inflammatory diseases including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. To date numerous bile acid derivatives have been identified as GPBAR1 agonists, however their clinical application is hampered by the lack of selectivity toward the other bile acid receptors. Therefore, non-steroidal GPBAR1 ligands able to selectively activate the receptor are urgently needed. With this aim, we here designed, synthesized and biologically evaluated ((1,2,4-oxadiazol-5-yl)pyrrolidin-3-yl) urea derivatives as novel potent GPBAR1 agonists. Particularly, compounds 9 and 10 induce the mRNA expression of the GPBAR1 target gene pro-glucagon and show high selectivity over the other bile acid receptors FXR, LXRα, LXRβ and PXR, and the related receptors PPARα and PPARγ. Computational studies elucidated the binding mode of 10 to GPBAR1, providing important structural insights for the design of non-steroidal GPBAR1 agonists. The pharmacokinetic properties of 9 and 10 suggest that the ((1,2,4-oxadiazol-5-yl)pyrrolidin-3-yl)ureydil scaffold might be exploited to achieve effective drug candidates to treat GPBAR1 related disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Discovery of ((1,2,4-oxadiazol-5-yl)pyrrolidin-3-yl)ureidyl derivatives as selective non-steroidal agonists of the G-protein coupled bile acid receptor-1

Leva

Festa

Carino³

et al. 2019

Sci Rep

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“…However, docking has signed an époque in which medicinal chemists have successfully combined docking calculations and experimental data to disclose the binding mode of many drugs and in turn explaining their mechanism of action. Furthermore, the elucidation of the intermolecular forces established by the ligand with its target, including salt bridges, H‐bonds and hydrophobic contacts, paves the way to rational modifications of its structure to achieve compounds with improved potency . This still poses docking calculations in a privileged position in structure–activity relationship (SAR) studies and structure‐based drug design.…”

Section: Docking Methodsmentioning

confidence: 99%

“…Furthermore, the elucidation of the intermolecular forces established by the ligand with its target, including salt bridges, H-bonds and hydrophobic contacts, paves the way to rational modifications of its structure to achieve compounds with improved potency. [53][54][55][56][57][58][59][60][61] This still poses docking calculations in a privileged position in structure-activity relationship (SAR) studies and structure-based drug design.…”

Section: Perspectivementioning

confidence: 99%

Ligand binding free energy and kinetics calculation in 2020

Limongelli

2020

WIREs Comput Mol Sci

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Ligand/protein binding (LPB) is a major topic in medicine, chemistry and biology. Since the advent of computers, many scientists have put efforts in developing theoretical models that could decode the alphabet of the LPB interaction. The success of this task passes by the resolution of the molecular mechanism of LPB. In the past century, major attention was dedicated to the thermodynamics of LPB, while more recent studies have revealed that ligand (un)binding kinetics is at least as important as ligand binding thermodynamics in determining the drug in vivo efficacy. In the present review, we introduce the most widely used computational methods to study LPB thermodynamics and kinetics. It is important to say that no method outperforms another, they all have pros and cons and the choice of the user should take carefully into account the system under investigation, the available structural and experimental data, and the goal of the research. A perspective on future directions of method development and research on LPB concludes the discussion. This article is categorized under: Molecular and Statistical Mechanics > Free Energy Methods Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods

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GPBAR1 Activation by C6-Substituted Hyodeoxycholane Analogues Protect against Colitis

Marino

Finamore

Biagioli³

et al. 2020

ACS Med. Chem. Lett.

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GPBAR1 agonists have been identified as potential leads for the treatment of diseases related to colon inflammation such as Crohn’s and ulcerative colitis. In this paper, we report the discovery of a small library of hyodeoxycholane analogues, decorated at C-6 with different substituents, as potent and selective GPBAR1 agonists. In vitro pharmacological assays showed that compound 6 selectively activates GPBAR1 (EC50 = 0.3 μM) and reduces the production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in THP1 cells. The binding mode of compound 6 in GPBAR1 was elucidated by docking calculations. Moreover, compound 6 protects against TNBS-induced colitis in Gpbar1+/+ rodent model, representing an intriguing lead for the treatment of these inflammatory disorders.

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Epoxide functionalization on cholane side chains in the identification of G-protein coupled bile acid receptor (GPBAR1) selective agonists

Abstract: Decoration of the bile acid side chain with an epoxide ring afforded potent and selective GPBAR1 agonists.

Cited by 4 publications

References 37 publications

Discovery of ((1,2,4-oxadiazol-5-yl)pyrrolidin-3-yl)ureidyl derivatives as selective non-steroidal agonists of the G-protein coupled bile acid receptor-1

Discovery of ((1,2,4-oxadiazol-5-yl)pyrrolidin-3-yl)ureidyl derivatives as selective non-steroidal agonists of the G-protein coupled bile acid receptor-1

Ligand binding free energy and kinetics calculation in 2020

GPBAR1 Activation by C6-Substituted Hyodeoxycholane Analogues Protect against Colitis

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