Natural modulators of nonalcoholic fatty liver disease: Mode of action analysis and in silico ADME-Tox prediction

Sharif, Merilin Al; Alov, Petko; Vitcheva, Vessela; Diukendjieva, Antonia; Mori, Mattia; Botta, Bruno; Tsakovska, Ivanka; Pajeva, Ilza

doi:10.1016/j.taap.2017.10.013

Cited by 13 publications

(4 citation statements)

References 109 publications

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“…In silico assessment of physicochemical properties and ADME predictions of the best active compound was carried out using ACD/Percepta v14.1.0 and SwissADME. , For the most promising novel Rolipram–Tranilast hybrids, a series of ADMET properties (absorption, distribution, metabolism, excretion, and toxicological properties) were calculated. In detail, we took into account the logarithmic ratio of the octanol–water partitioning coefficient (clog P), molecular weight (MW), rotatable bonds, H-bond acceptors, H-bond donors (Lipinski’s Rule of Five), Caco2 (derived from human colon adenocarcinoma cells) permeability, and CNS penetration scores. , As shown in Table , compound 5 was predicted to reach the CNS, being characterized by adequate lipophilicity values and followed the Lipinski’s rules.…”

Section: Results and Discussionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Multifunctional Rolipram–Tranilast Hybrids As Potential Treatment for Traumatic Brain Injury

Chen

Deng

et al. 2020

ACS Chem. Neurosci.

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Traumatic brain injury (TBI) is a prevalent public healthcare concern frequently instigated by mechanical shock, traffic, or violence incidents, leading to permanent nerve damage, and there is no ideal treatment for it yet. In this study, a series of Rolipram–Tranilast hybrids were designed and synthesized. The neuroprotective activities of the Rolipram–Tranilast hybrids were evaluated both in vitro and in vivo. Compound 5 has been identified as the strongest neuroprotective molecule among the series with robust anti-oxidant and anti-inflammatory potentials. Compound 5 significantly increased the heme oxygenase-1 (HO-1) levels and the phosphorylated cAMP response elements binding protein (p-CREB) while it down-regulated phosphodiesterase-4 B (PDE4B) expression in vitro. Furthermore, compound 5 remarkably attenuated TBI and had a good safety profile in mice. Taken together, our findings suggested that compound 5 could serve as a novel promising lead compound in the treatment of TBI and other central nervous system (CNS) diseases associated with PDE4B and oxidative stress.

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Section: Results and Discussionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Multifunctional Rolipram–Tranilast Hybrids As Potential Treatment for Traumatic Brain Injury

Chen

Deng

et al. 2020

ACS Chem. Neurosci.

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“…A knowledge-based approach to rank metabolites based on known metabolic reactions . To predict the first metabolic step of contilisant, we analyze the Phase I biotransformation pathways, combining two different methods . A qualitative [absolute reasoning (AR)] and quantitative [site of metabolism (SOM) scoring] assessment was applied, selecting the matching metabolites.…”

Section: Methodsmentioning

confidence: 99%

“…19 To predict the first metabolic step of contilisant, we analyze the Phase I biotransformation pathways, combining two different methods. 27 A qualitative [absolute reasoning (AR)] and quantitative [site of metabolism (SOM) scoring] assessment was applied, selecting the matching metabolites. The AR evaluated the likelihood level for biotransformation to occur, and the minimal likelihood level was settled in "plausible," which means that the weight of evidence supports the proposition.…”

Section: Methodsmentioning

confidence: 99%

In Vitro and In Silico ADME-Tox Profiling and Safety Significance of Multifunctional Monoamine Oxidase Inhibitors Targeting Neurodegenerative Diseases

Więckowska

Szałaj

Góral

et al. 2020

ACS Chem. Neurosci.

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Herein we report in vitro metabolic stability in human liver microsomes (HLMs), interactions with cytochrome P450 isoenzymes (CYP3A4, CYP2D6, and CYP2C9), and cytotoxicity analyses on HEK-293, HepG2, Huh7, and WTIIB cell lines of our most recent multitarget directed ligands PF9601N, ASS234, and contilisant. Based on these results, we conclude that (1) PF9601N and contilisant are metabolically stable in the HLM assay, in contrast to the very unstable ASS234; (2) CYP3A4 activity was decreased by PF9601N at all the tested concentrations and by ASS234 and contilisant only at the highest concentration; CYP2D6 activity was reduced by ASS234 at 1, 10, and 25 μM and by PF9601N at 10 and 25 μM, whereas contilisant increased its activity at the same concentrations; CYP2C9 was inhibited by the three compounds; (3) contilisant did not affect cell viability in the widest range of concentrations: up to 10 μM on HEK-293 cells, up to 30 μM on Huh7 cells, up to 50 μM on HepG2 cells, and up to 30 or 100 μM on WTIIB cells. Based on these results, we selected contilisant as a metabolically stable and nontoxic lead compound for further studies in Alzheimer's disease therapy.

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“…To predict metabolism, we use Meteor Nexus v 3.1.0 (knowledge base 2018 1.0.0), a knowledge-based approach to rank metabolites based on known metabolic reactions 78 . To predict first metabolic step of the parent compound (hybrid 6 ), we analysed the phase-I biotransformation pathways, combining two different methods 80 . A qualitative [absolute reasoning (AR)] and quantitative (site of metabolism (SOM) scoring) assessment was applied, selecting the matching metabolites.…”

Section: Methodsmentioning

confidence: 99%

New flavonoid –N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer´s disease endowed with neurogenic properties

Estrada-Valencia¹,

Herrera-Arozamena²,

Pérez³

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N , N -dibenzyl( N -methyl)amine (DBMA) fragments, new CNS-permeable flavonoid – DBMA hybrids ( 1 – 13 ) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer’s disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), β-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (σ 1 R/σ 2 R). After a funnel-type screening, 6,7-dimethoxychromone – DBMA ( 6 ) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and σ 1 R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6 , which could synergistically contribute to neuronal regeneration and block neurodegeneration.

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Natural modulators of nonalcoholic fatty liver disease: Mode of action analysis and in silico ADME-Tox prediction

Cited by 13 publications

References 109 publications

Design, Synthesis, and Biological Evaluation of Novel Multifunctional Rolipram–Tranilast Hybrids As Potential Treatment for Traumatic Brain Injury

Design, Synthesis, and Biological Evaluation of Novel Multifunctional Rolipram–Tranilast Hybrids As Potential Treatment for Traumatic Brain Injury

In Vitro and In Silico ADME-Tox Profiling and Safety Significance of Multifunctional Monoamine Oxidase Inhibitors Targeting Neurodegenerative Diseases

New flavonoid –N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer´s disease endowed with neurogenic properties

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