In silico analysis of selected polyphenols as potential multitarget rheumatoid arthritis modifying agents

TL;DR

This study explores six polyphenols as potential multitarget treatments for rheumatoid arthritis, showing they have better pharmacokinetic properties and target key inflammatory pathways compared to methotrexate.

Contribution

The study introduces six polyphenols as multitarget rheumatoid arthritis modifiers with favorable pharmacokinetics and broad pathway modulation.

Findings

All six polyphenols met Lipinski's criteria and showed better pharmacokinetic properties than methotrexate.

Catechin, piceatannol, galangin, and umbelliferone demonstrated strong binding affinities to key RA targets like iNOS, COX-2, and MMP-9.

Network analysis revealed modulation of critical inflammatory pathways including TNF, IL-17, JAK–STAT, and NF-κB.

Abstract

Rheumatoid arthritis (RA) arises from a complex inflammatory network involving cytokines, kinases, and matrix degrading enzymes. Methotrexate is the clinical standard but is limited by poor pharmacokinetics and a narrow mechanism.

This study evaluates six polyphenols sinapic acid, catechin, galangin, piceatannol, umbelliferone, and pinocembrin against fifteen validated RA targets and benchmarks them against methotrexate.An integrated in silico framework assessed ADME properties, molecular docking, and network pharmacology. ADME screening included Lipinski compliance, GI absorption, solubility, CYP450, and bioavailability.

All polyphenols fullfill Lipinski’s criteria and showed moderate lipophilicity, high predicted GI absorption, favourable solubility, minimal CYP450 interactions, and bioavailability scores of 0.55. Methotrexate displayed one rule violation, extreme hydrophilicity, poor permeability, low GI absorption, and a bioavailability score of 0.11. Docking confirmed methotrexate as the strongest single-target binder; however, catechin, piceatannol, galangin, and umbelliferone demonstrated strong affinities (–6.1 to –9.9 kcal/mol), particularly to iNOS, COX-2, and MMP-9. Network analysis highlighted modulation of TNF, IL-17, JAK–STAT, NF-κB, RA, and arachidonic-acid pathways and GO linked to inflammation and matrix degradation.

The polyphenols, in combination with catechin, are pharmacokinetically robust multitarget modulators capable of suppressing cytokine signalling, kinase activation, NF-κB transcription, and matrix degradation, therefore positing these phytochemicals as promising for next-generation RA therapeutics.

The online version contains supplementary material available at 10.1007/s11033-026-11440-7.

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