Identification of the anti-fungal drug fenticonazole nitrate as a novel PPARγ-modulating ligand with good therapeutic index: Structure-based screening and biological validation

Ma, Lei; Lian, Yuling; Tang, Junyuan; Chen, Fangyuan; Gao, Hui; Zhou, Zhi; Hou, Ning; Yi, Wei

doi:10.1016/j.phrs.2021.105860

Cited by 9 publications

(3 citation statements)

References 51 publications

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“…Interestingly, on the other hand, high concentrations of lansoprazole strongly inhibited differentiation and expression of PPARγ and CEBPA and maintained the expression of the preadipocytes markers, β-catenin, and PREF-1 [ 89 ]. It is also possible to seek new ligands with high throughput screening, such as the antifungal drug fenticonazole nitrate, which has been identified as a new potent PPARγ-modulating ligand to significantly demonstrate antidiabetic and anti-nonalcoholic fatty liver disease, using, among others, adipocyte differentiation assays with 3T3-L1 cells and molecular docking validation [ 90 ]. However, the results obtained with animal models and non-human cell lines may not be adequately translated to humans due to interspecies differences [ 91 ], a significant drawback of 3T3-L1 utilization for obesity studies.…”

Section: Alternative Methods To Animal Testing In Adipogenesismentioning

confidence: 99%

Alternative Methods as Tools for Obesity Research: In Vitro and In Silico Approaches

Pamplona

Zoehler²,

Shigunov³

et al. 2022

Life

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The study of adipogenesis is essential for understanding and treating obesity, a multifactorial problem related to body fat accumulation that leads to several life-threatening diseases, becoming one of the most critical public health problems worldwide. In this review, we propose to provide the highlights of the adipogenesis study based on in vitro differentiation of human mesenchymal stem cells (hMSCs). We list in silico methods, such as molecular docking for identification of molecular targets, and in vitro approaches, from 2D, more straightforward and applied for screening large libraries of substances, to more representative physiological models, such as 3D and bioprinting models. We also describe the development of physiological models based on microfluidic systems applied to investigate adipogenesis in vitro. We intend to identify the main alternative models for adipogenesis evaluation, contributing to the direction of preclinical research in obesity. Future directions indicate the association of in silico and in vitro techniques to bring a clear picture of alternative methods based on adipogenesis as a tool for obesity research.

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Section: Alternative Methods To Animal Testing In Adipogenesismentioning

confidence: 99%

Alternative Methods as Tools for Obesity Research: In Vitro and In Silico Approaches

Pamplona

Zoehler²,

Shigunov³

et al. 2022

Life

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“…It can be seen that there are no significant differences in their docking positions. [35] This is probably due to the reason that docked compounds are very similar in structure to each other with slight difference of position of halogens.…”

Section: Binding Energy and Intermolecular Analysismentioning

confidence: 99%

Synthesis and Computational Exploration of Morpholine Bearing Halogenated Sulfonamides as Potential Tyrosinase Inhibitors

Abbasi

Raza

Siddiqui

et al. 2023

Chemistry & Biodiversity

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In the presented work, a novel series of three different 4‐((3,5‐dichloro‐2‐[(2/4‐halobenzyl)oxy]phenyl)sulfonyl)morpholines was synthesized and the structure of these compounds were corroborated by 1H‐NMR & 13C‐NMR studies. The in vitro results established all the three compounds as potent tyrosinase inhibitors relative to the standard. The Kinetics mechanism plots established that compound 8 inhibited the enzyme non‐competitively. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0025µM. Additionally, computational techniques were used to explore electronic structures of synthesized compounds. Fully optimized geometries were further docked with tyrosinase enzyme for inhibition studies. Reasonably good binding/interaction energies and intermolecular interactions were obtained. Finally, drug likeness was also predicted using the rule of five (RO5) and Chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics. It is anticipated that current experimental and computational investigations will evoke the scientific interest of the research community for the above‐entitled compounds.

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“…The pharmacological investigation of fenticonazole ( 23 ) showed such desired drug properties primarily by potently activating the expressions of adiponectin and GLUT4, inhibiting the expressions of TNF-α, IL-6, and IL-1, blocking PPAR Ser273 phosphorylation that leads to adipogenesis without mediation by CDK5 and inducing the expressions of key adipogenic genes CD36, LPL, AP2, FASN, C/EBP, and PPARγ. Molecular docking validation was also performed at the active site of PPARγ (PDB code: 6MS7) using the CDOCKER mode in Discovery Studio 3.1, resulting in a promising binding mode between the fenticonazole and ligand-binding site of PPARγ, which included a hydrogen-bonding network between the oxygen, sulfur, and nitrogen atoms of fenticonazole and the PPARγ residues Tyr327, Cys285, and Ser342 [ 98 ].…”

Section: Recent Developments In the Medicinal Chemistry Of Pparsmentioning

confidence: 99%

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

et al. 2022

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The family of nuclear peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) is a set of ligand-activated transcription factors that regulate different functions in the body. Whereas activation of PPARα is known to reduce the levels of circulating triglycerides and regulate energy homeostasis, the activation of PPARγ brings about insulin sensitization and increases the metabolism of glucose. On the other hand, PPARβ when activated increases the metabolism of fatty acids. Further, these PPARs have been claimed to be utilized in various metabolic, neurological, and inflammatory diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity. A series of different heterocyclic scaffolds have been synthesized and evaluated for their ability to act as PPAR agonists. This review is a compilation of efforts on the part of medicinal chemists around the world to find novel compounds that may act as PPAR ligands along with patents in regards to PPAR ligands. The structure–activity relationship, as well as docking studies, have been documented to better understand the mechanistic investigations of various compounds, which will eventually aid in the design and development of new PPAR ligands. From the results of the structural activity relationship through the pharmacological and in silico evaluation the potency of heterocycles as PPAR ligands can be described in terms of their hydrogen bonding, hydrophobic interactions, and other interactions with PPAR.

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Identification of the anti-fungal drug fenticonazole nitrate as a novel PPARγ-modulating ligand with good therapeutic index: Structure-based screening and biological validation

Cited by 9 publications

References 51 publications

Alternative Methods as Tools for Obesity Research: In Vitro and In Silico Approaches

Alternative Methods as Tools for Obesity Research: In Vitro and In Silico Approaches

Synthesis and Computational Exploration of Morpholine Bearing Halogenated Sulfonamides as Potential Tyrosinase Inhibitors

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

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