Antirheumatic Potential of Araucaria-Derived Biflavonoids through In Silico Docking to 20S Proteasome
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Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, often treated with drugs targeting a single pathway. Biflavonoids, such as isoginkgetin, have been reported to modulate multiple inflammatory pathways by inhibiting the 20S proteasome. This study employed molecular docking to evaluate 23 biflavonoid ligands from the Araucaria genus as potential proteasome inhibitors (PDB ID: 5LE5 and 5LF7). The results showed that ochnaflavone (BF23) exhibited the best binding affinity (-11.48 and -10.47 kcal/mol) but displayed unfavorable pharmacokinetic and toxicity profiles. Meanwhile, 7′′-O-methylamentoflavone (BF11) variant 2 (-10.64 kcal/mol) and 7,7′′-di-O-methylamentoflavone (BF12) variant 4 (-10.49 kcal/mol) were identified as promising inhibitors for 5LE5, while BF11 variant 3 (-10.00 kcal/mol), BF12 variant 2 (-9.75 kcal/mol), 7,4′-di-O-methylamentoflavone (BF14) variant 5 (9.82 kcal/mol), and 7,4′,7′′-tri-O-methylamentoflavone (BF9) variant 2 (-9.66 kcal/mol) exhibited strong binding to 5LF7. The presence of methoxy (-OCH3) groups at the 7 and/or 7′′ positions in amentoflavone derivatives are predicted to significantly influence their inhibitory activity. BF23 variants 2 and 5 occupied distinct active sites, with 5LE5 ligands predominantly interacting with the β1 subunit (L chain) and 5LF7 ligands engaging the β5 subunit (K chain). These findings suggest that biflavonoids from Araucaria could serve as promising candidates for anti-RA drug development, targeting both β1 and β5 proteasome subunits.
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