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Methotrexate is the clinical standard but is limited by poor pharmacokinetics and a narrow mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All polyphenols fullfill Lipinski\u2019s 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 (\u20136.1 to \u20139.9 kcal\/mol), particularly to iNOS, COX-2, and MMP-9. Network analysis highlighted modulation of TNF, IL-17, JAK\u2013STAT, NF-\u03baB, RA, and arachidonic-acid pathways and GO linked to inflammation and matrix degradation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The polyphenols, in combination with catechin, are pharmacokinetically robust multitarget modulators capable of suppressing cytokine signalling, kinase activation, NF-\u03baB transcription, and matrix degradation, therefore positing these phytochemicals as promising for next-generation RA therapeutics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11033-026-11440-7","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:11:23Z","timestamp":1768565483000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In silico analysis of selected polyphenols as potential multitarget rheumatoid arthritis modifying agents"],"prefix":"10.1007","volume":"53","author":[{"given":"Shiva","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudheesh K.","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna K.","family":"Govender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penny P.","family":"Govender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"11440_CR1","doi-asserted-by":"crossref","unstructured":"Kumari M, Sadhu P, Shah N, Talele C, Gohil D (2024) Comprehensive review of rheumatoid arthritis: insights, challenges, and prospects. 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We confirm that this manuscript is original, has not been published previously, and is not under consideration elsewhere.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"<!--Emphasis Type='Bold' removed-->Consent to Participate and Publication"}},{"value":"The authors declare that they have followed the ethical guidelines outlined by the journal and that this study was conducted with the utmost respect for the rights and dignity of all participants. However, there is no requirement for the formal ethical approval as results are based on the in silico studies, with no human involvement.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"<!--Emphasis Type='Bold' removed-->Ethical Approval"}}],"article-number":"297"}}