Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists

Festa, Carmen; Finamore, Claudia; Marchianò, Silvia; Leva, Francesco Saverio Di; Carino, Adriana; Monti, Maria Chiara; Gaudio, Federica Del; Ceccacci, Sara; Limongelli, Vittorio; Zampella, Angela; Fiorucci, Stefano; Marino, Simona De

doi:10.1021/acsmedchemlett.8b00534

Cited by 28 publications

(27 citation statements)

References 22 publications

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“…After activation, FXR in complex with the retinoid X receptor (RXR) binds to DNA regulating the expression of proteins involved in bile acid synthesis, triglyceride clearance, cholesterol reduction and modulating insulin sensitivity 56,57 . Therefore, in recent years FXR has become a prominent target for treatment of metabolic disorders, primary biliary cirrhosis, and non-alcoholic steatohepatitis syndrome 58,59 . Here, we investigate the binding of the potent agonist 6-ethyl-chenodeoxycholic acid (also known as obeticholic acid) to FXR.…”

Section: Resultsmentioning

confidence: 99%

Protein–ligand binding with the coarse-grained Martini model

et al. 2020

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The detailed understanding of the binding of small molecules to proteins is the key for the development of novel drugs or to increase the acceptance of substrates by enzymes. Nowadays, computer-aided design of protein-ligand binding is an important tool to accomplish this task. Current approaches typically rely on high-throughput docking essays or computationally expensive atomistic molecular dynamics simulations. Here, we present an approach to use the recently re-parametrized coarse-grained Martini model to perform unbiased millisecond sampling of protein-ligand interactions of small drug-like molecules. Remarkably, we achieve high accuracy without the need of any a priori knowledge of binding pockets or pathways. Our approach is applied to a range of systems from the wellcharacterized T4 lysozyme over members of the GPCR family and nuclear receptors to a variety of enzymes. The presented results open the way to high-throughput screening of ligand libraries or protein mutations using the coarse-grained Martini model.

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Section: Resultsmentioning

confidence: 99%

Protein–ligand binding with the coarse-grained Martini model

et al. 2020

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“…To confirm that a dysregulated FXR signaling was responsible for the defective autophagy regulation in response to fasting observed in Gpbar1 −/− mice, unfed wild‐type, and Gpbar1 −/− mice were challenged with GP7, a potent and selective FXR antagonist 29 . As shown in Figure 2, the exposure of wild‐type mice to 16 hours fasting alone promoted a further induction of the expression of autophagic genes Atg5, Atg7, Atg12, Lc3, Pgc1α, and Ppparα in both epididymal white adipose tissue (eWAT) and liver.…”

Section: Resultsmentioning

confidence: 99%

“…BAR501 (6β-ethyl-3a,7b-dihydroxy-5b-cholan-24-ol), BAR704, and GP7 were synthesized as described elsewhere. [28][29][30] 3-iso-butyl-1-methylxanthine (IBMX), dexamethasone, and insulin were purchased from Sigma Aldrich (Milan, Italy).…”

Section: Chemicalsmentioning

confidence: 99%

The bile acid activated receptors GPBAR1 and FXR exert antagonistic effects on autophagy

et al. 2020

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Autophagy is a highly conserved catabolic process activated by fasting and caloric restriction. FXR, a receptor for primary bile acids, reverses the activity of cAMP‐response element binding protein (CREB) on autophagy‐related genes (Atg)s and terminates autophagy in the fed state. GPBAR1, a receptor for secondary bile acids, exerts its genomic effects via cAMP‐CREB pathway. By genetic and pharmacological approaches, we have obtained evidence that GPBAR1 functions as a positive modulator of autophagy in liver and white adipose tissue (WAT) in fasting. Mechanistically, we found that Gpbar1−/− mice lack the expression of Cyp2c70 a gene essential for generation of muricholic acids which are FXR antagonists, and have an FXR‐biased bile acid pool. Because FXR represses autophagy, Gpbar1−/− mice show a defective regulation of autophagy in fasting. BAR501, a selective GPBAR1 agonist, induces autophagy in fed mice. Defective regulation of autophagy in Gpbar1−/− could be reversed by FXR antagonism, while repression of autophagy by feeding was partially abrogated by FXR gene ablation, and FXR activation repressed Atgs in the fast state. BAR501 reversed the negative regulatory effects of feeding and FXR agonism on autophagy and promoted the recruitment of CREB to a CRE on the LC3 promoter. In mice exposed to chronic high caloric intake, GPBAR1 agonism ameliorated insulin sensitivity and induced Atgs expression in the liver and WAT. In summary, GPBAR1 is required for positive regulation of autophagy in fasting and its ligands reverse the repressive effects exerted on liver and WAT autophagy flow by FXR in fed.

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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%

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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Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists

Cited by 28 publications

References 22 publications

Protein–ligand binding with the coarse-grained Martini model

Protein–ligand binding with the coarse-grained Martini model

The bile acid activated receptors GPBAR1 and FXR exert antagonistic effects on autophagy

Ligand binding free energy and kinetics calculation in 2020

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