<![CDATA[Long-term use of NSAIDs is associated with gastrointestinal and cardiovascular adverse effects. That persistent problem has pushed a lot of research toward natural molecules that reduce inflammation with fewer adverse effects. Flavonoids have garnered significant attention because many are active and safe, however, the precise mechanism by which flavonoids interact with cyclooxygenase‑2 (COX‑2) has not yet been fully elucidated through molecular docking. We selected six of them, quercetin, kaempferol, apigenin, myricetin, luteolin, and genistein, and docked each into the COX‑2 crystal structure (PDB ID: 3LN1) using UCSF DOCK6. Celecoxib was the reference. The co‑crystallized ligand was re‑docked first; the RMSD came out at 0.774 Å. That sits comfortably below the 2.40 Å acceptance limit, so the protocol was reliable for the rest of the work. Quercetin bound tightest: its Grid Score reached –36.36 kcal/mol, roughly 63.4% of the celecoxib score. Kaempferol (–36.25 kcal/mol) and apigenin (–34.69 kcal/mol) were close behind. Inside the active site, quercetin formed five hydrogen bonds, and additional Pi‑alkyl plus van der Waals contacts kept it firmly in place. When we checked drug‑likeness, all six flavonoids met Lipinski's rule of five except myricetin; its topological polar surface area hit 147.68 Ų, causing a single violation. Blood‑brain barrier penetration was estimated from PSA values. Quercetin, kaempferol, myricetin, and luteolin all have PSA above 90 Ų, so meaningful brain entry is unlikely, precisely what we would consider ideal for a peripheral anti‑inflammatory agent. Apigenin and genistein (PSA 86.99 Ų) sit right at the threshold. Quercetin and kaempferol stand out as the strongest leads for peripheral anti‑inflammatory therapy, and the next logical steps are in vitro COX‑2 inhibition assays followed by preclinical testing.]]>
