Computational profiling of anti-inflammatory phytochemicals targeting 5-LOX and COX-2 pathways: PASS prediction,...

This study computationally evaluates six phytochemicals (piperine, ardisiaquinone A, genistein, cianidanol, liquiritigenin, and rosmarinic acid) for their anti-inflammatory potential targeting 5-LOX and COX-2 pathways. PASS prediction analysis revealed that all phytochemicals, except piperine, met the threshold for significant anti-inflammatory activity (Pa > Pi and Pa ≥0.5). Among them, genistein (Pa = 0.626) and liquiritigenin (Pa = 0.616) demonstrated the highest probabilities, indicating strong potential as anti-inflammatory agents. The phytochemicals showed strong binding to 5-LOX (-7.6 to -8.7 kcal/mol) and COX-2 (-8.8 to -10.2 kcal/mol), with cianidanol, piperine and ardisiaquinone A forming stable interactions in catalytic sites through hydrogen bonds and hydrophobic contacts. Their binding energies were comparable to the reference drug indomethacin (-7.9 kcal/mol for 5-LOX and -10.0 kcal/mol for COX-2), validating their inhibitory potential against these inflammatory enzymes. ADMET profiling highlighted cianidanol as the lead candidate, exhibiting optimal permeability (Caco-2: -6.052), low CYP/hERG risks, and negligible toxicity, whereas piperine and rosmarinic acid showed concerning CYP3A4 inhibition (0.936) and cardiotoxicity (hERG: 0.856). Molecular dynamics simulations (100 ns) confirmed the stability of key complexes (RMSD <2.0 Å). These results, supported by MM-PBSA binding energy calculations (-40.2 to -44.9 kcal/mol), propose cianidanol and liquiritigenin as structurally stable, low-risk candidates for further experimental validation.