<i>Gallic</i>, <i>Aconitic</i>, and <i>Crocetin</i> Acids as Potential TNF Modulators: An Integrated Study Combining Molecular Docking, Dynamics Simulations, ADMET Profiling, and Gene Expression Analysis

<i>Gallic</i>, <i>Aconitic</i>, and <i>Crocetin</i> Acids as Potential TNF Modulators: An Integrated Study Combining Molecular Docking, Dynamics Simulations, ADMET Profiling, and Gene Expression Analysis

Organic acids, as natural metabolites, play crucial roles in human metabolism and health. Tumor Necrosis Factor (TNF), a pivotal mediator in immune regulation and inflammation, is a key therapeutic target. We evaluated ten organic acids as TNF modulators using in silico molecular docking, followed b...

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Bibliographic Details
Main Authors: Adolat Manakbayeva, Andrey Bogoyavlenskiy, Timur Kerimov, Igor Yershov, Pavel Alexyuk, Madina Alexyuk, Vladimir Berezin, Vyacheslav Dushenkov
Format: Article
Language:English
Published: MDPI AG 2025-07-01
Series:Molecules
Subjects:
TNF
immunomodulator
molecular docking
ADMET
gene expression
Online Access:https://www.mdpi.com/1420-3049/30/15/3175
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Summary:Organic acids, as natural metabolites, play crucial roles in human metabolism and health. Tumor Necrosis Factor (TNF), a pivotal mediator in immune regulation and inflammation, is a key therapeutic target. We evaluated ten organic acids as TNF modulators using in silico molecular docking, followed by detailed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling and molecular dynamics (MD) simulations for three lead candidates: <i>gallic</i>, <i>aconitic</i>, and <i>crocetin</i> acids. Their effects on TNF gene expression were then assessed <i>in vivo</i> using a mouse leukocyte model. The in silico results indicated that <i>crocetin</i> had the highest TNF binding affinity (−5.6 to −4.6 kcal/mol), while <i>gallic</i> acid formed the most stable protein-ligand complex during MD simulations, and <i>aconitic</i> acid established hydrogen bond interactions. ADMET analysis suggested potential pharmacokinetic limitations, including low permeability. Contrasting its high predicted binding affinity, <i>in vivo</i> gene expression analysis revealed that <i>crocetin</i> stimulated TNF synthesis, whereas <i>gallic</i> and <i>aconitic</i> acids acted as inhibitors. This research explores organic acids as potential TNF modulators, highlighting their complex interactions and providing a foundation for developing these compounds as anti-inflammatory agents targeting TNF-mediated diseases.
ISSN:1420-3049

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