Institutional Repository UIN Sunan Kalijaga YogyakartaSTUDI IN SILICO TURUNAN LUTEOLIN TERFLUORINASI SEBAGAI KANDIDAT INHIBITOR CYCLOOXYGENASE-2 (COX-2) MENGGUNAKAN METODE MOLECULAR DOCKING DAN ANALISIS ADMETNIM.: 19106030017Miftachul JannahauthorLuteolin is a flavonoid compound with anti-inflammatory activity through inhibition of cyclooxygenase-2 (COX-2); however, its utilization as a drug candidate is limited by its low water solubility and limited oral bioavailability. Fluorination of the catechol group at positions 3′ and 4′ of the B ring of luteolin was investigated as a structural modification strategy to evaluate its effects on binding affinity, molecular interaction patterns, and ADMET profiles toward COX-2. This study aimed to analyze the effects of fluorine atom substitution at these positions on binding affinity and interaction patterns with COX-2, as well as to predict and compare the ADMET and drug-likeness profiles of 3′-fluoroluteolin and 4′-fluoroluteolin with those of luteolin. Molecular docking was performed using AutoDock Vina against the crystal structure of COX-2 (PDB ID: 5IKR), with etoricoxib as the positive control, preceded by method validation through redocking of the native ligand (RMSD 0.484 Å). ADMET profiles were predicted using SwissADME, pkCSM, and ProTox-3.0. The docking results showed that luteolin had a more negative binding affinity (−9.123 kcal/mol) than 3′-fluoroluteolin (−8.611 kcal/mol) and 4′- fluoroluteolin (−8.583 kcal/mol); however, luteolin did not interact with key residues of the COX-2 active site (Arg120, Tyr355, Tyr385, Ser530, and Val523), whereas 4′-fluoroluteolin formed a hydrogen bond with Ser530 and a pi-alkyl interaction with Val523, exhibiting an interaction pattern most similar to those of the native ligand and etoricoxib. Fluorination decreased HBD and TPSA and increased LogP without violating the Lipinski or Veber rules, accompanied by increased intestinal absorption. However, both derivatives were predicted to be active for hepatotoxicity, in contrast to luteolin, which was inactive; conversely, both derivatives were predicted to be inactive for carcinogenicity and mutagenicity (Ames), in contrast to luteolin, which was active. These results indicate that the effects of fluorination on binding affinity and ADMET profiles are position-dependent and involve a toxicological trade-off that requires further in vitro validation.540 Kimia2026-08-14UIN SUNAN KALIJAGA YOGYAKARTA;FAKULTAS SAINS DAN TEKNOLOGIThesis

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