Novel Isoxazole Derivatives with Potent FXR Agonistic Activity Prevent Acetaminophen-Induced Liver Injury

Sepe, Valentina; Marchianò, Silvia; Finamore, Claudia; Baronissi, Giuliana; Leva, Francesco Saverio Di; Carino, Adriana; Biagioli, Michele; Chiara, Federica; Cassiano, Chiara; Monti, Maria Chiara; Gaudio, Federica Del; Novellino, Ettore; Limongelli, Vittorio; Fiorucci, Stefano; Zampella, Angela

doi:10.1021/acsmedchemlett.8b00423

Cited by 28 publications

(17 citation statements)

References 29 publications

(44 reference statements)

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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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“…[ 33,45–48 ] However, chlorophenyl derivatives may enhance potency and binding efficiency compared to their unsubstituted phenyl derivatives. [ 2,49,50 ] In addition, these derivatives show an improvement in metabolic stability and pharmacokinetic profile, as recently demonstrated by Eggert et al, [ 49 ] who identified that the 3,4‐dichloro derivative (IC 50 = 0.08 μM) is more active than the corresponding 4‐chloro (IC 50 = 0.8 μM) and unsubstituted phenyl derivatives (IC 50 > 20 μM) against SMYD2 for the treatment of cancer. To test this hypothesis, we decided to synthesize the novel N ‐phenyl and N ‐3,5‐dichlorophenyl derivatives to evaluate the effect of the aryl and the chlorine substituents on biological activities.…”

Section: Resultsmentioning

confidence: 79%

New thiazolyl‐pyrazoline derivatives bearing nitrogen mustard as potential antimicrobial and antiprotozoal agents

Cuartas

Robledo

Vélez

et al. 2020

Archiv der Pharmazie

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A new series of N-substituted pyrazoline derivatives 6a-g, 7a-g, 8a-g, and 9a-g was synthetized by reaction of hydrazine derivatives and chalcone-thiazole hybrids bearing nitrogen mustard 5a-g. The chalcones 5a-g were obtained by Claisen-Schmidt condensation of thiazole-2-nitrogen mustard 3 and selected acetophenones 4a-g. These new compounds 6/7/8/9a-g were screened for their antifungal activity against Cryptococcus neoformans, with IC 50 values of 3.9-7.8 µg/ml for the N-3, 5-dichlorophenyl pyrazolines 9e-g. Interestingly, those compounds show low cytotoxic effects toward erythrocytes (RBC). In addition, N-acetyl (6a,b) and N-formyl pyrazolines (7a, 7b, 7c, and 7g) showed inhibitory activity against methicillinsusceptible Staphylococcus aureus, methicillin-resistant S. aureus, and vancomycinintermediate S. aureus, with the most important minimum inhibitory concentration values ranging from 31.25 to 125 µg/ml. Regarding the antiprotozoal activity, thiazolyl-pyrazolines 9g, 8f, and 7c display high activity against Plasmodium falciparum, Leishmania (V) panamensis, and Trypanosoma cruzi, with EC 50 values of 11.80, 6.46, and 4.98 μM, respectively, and with 7c being approximately 2.6-fold more potent than benznidazole with a selectivity index of 1.61 on U-937 human cells, showing promising potential as a novel antitrypanosomal agent. K E Y W O R D S antibacterial activity, antifungal activity, antiprotozoal activity, chalcone, pyrazoline

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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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Novel Isoxazole Derivatives with Potent FXR Agonistic Activity Prevent Acetaminophen-Induced Liver Injury

Cited by 28 publications

References 29 publications

Protein–ligand binding with the coarse-grained Martini model

Protein–ligand binding with the coarse-grained Martini model

New thiazolyl‐pyrazoline derivatives bearing nitrogen mustard as potential antimicrobial and antiprotozoal agents

Ligand binding free energy and kinetics calculation in 2020

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