COX-2/5-LOX dual inhibitors represent an innovative strategy in the development of
nonsteroidal anti-inflammatory drugs (NSAIDs). These compounds simultaneously target
cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzymes, effectively impeding the
production of inflammatory mediators in the cyclooxygenase and lipoxygenase pathways. This
dual inhibition approach enhances therapeutic efficacy while minimizing the adverse effects
associated with COX-2 and 5-LOX inhibition. In this study, a comprehensive screening of
1022 molecules (analogues of compound 52) led to the identification of 18 promising COX-
2/5-LOX inhibitors. The selection process involved quantitative structure-activity relationship
(QSAR) analysis, utilizing 62 known inhibitors, virtual screening, molecular docking
techniques, and in silico pharmacokinetic assessment. The 2D QSAR models for COX-2 and
5-LOX inhibition demonstrated high predictive accuracy (COX-2: R2=0.9308, Q2=0.8936; 5-
LOX: R2=0.9209, Q2=0.8879). Docking studies further elucidated the binding affinity and
specific interactions between the identified compounds and COX-2/5-LOX proteins, revealing
robust hydrophobic and hydrogen bonding forces at play. ADMET analysis highlighted
molecules VS864, VS865, VS882, VS888, VS895, VS896, VS897, and VS898 as optimal
candidates, meeting all current drug-likeness criteria without posing any hazardous impacts.
Molecular dynamic simulations confirmed the binding stabilities of the selected compounds. Consequently, compounds VS864, VS865, VS882, VS888, VS895, VS896, VS897, and
VS898 emerge as potential COX-2/5-LOX dual inhibitor candidates, paving the way for further
evaluation in therapeutic applications.
Keywords: COX-2/5-LOX dual inhibitors, QSAR, virtual screening, molecular docking,
pharmacokinetic analysis, Molecular Dynamic simulations
Publication date: 01/03/2025
https://ijbpas.com/pdf/2025/March/MS_IJBPAS_2025_8828.pdf
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https://doi.org/10.31032/IJBPAS/2025/14.3.8828
