, , and 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 by detailed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling and molecular dynamics (MD) simulations for three lead candidates: , , and acids. Their effects on TNF gene expression were then assessed using a mouse leukocyte model. The in silico results indicated that had the highest TNF binding affinity (-5.6 to -4.6 kcal/mol), while acid formed the most stable protein-ligand complex during MD simulations, and acid established hydrogen bond interactions. ADMET analysis suggested potential pharmacokinetic limitations, including low permeability. Contrasting its high predicted binding affinity, gene expression analysis revealed that stimulated TNF synthesis, whereas and 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.