Molecular Docking of Seed Bioactives as Dual COX-2 and LOX-3 Inhibitors in Context to Osteoarthritis

Introduction: Potent anti-inflammatory seed bioactives through dual inhibition of cyclooxygenase (COX)-2 and lipoxygenase (LOX)-3 were evaluated by a computational approach, routinely used to reduce cost and time in drug discovery. Methods: The strategy employed in this study could be split into the two categories of screening and docking. Results: The analysis resulted in seven Lipinski compliant hits (epicatechin, 3, 4-Dihydroxy phe- nyl acetic acid, gallic acid, 3, 4-Dihydroxy benzoate, procyanidin, ascorbic acid, oxacyclohexadecan-2-one, 16 ethyl). They were docked to the crystal structure of COX-2; 1PXX and LOX-3; 1JNQ and scored to identify structur- ally novel ligands that make similar interaction to the known ligands (diclof- enac) and many have different interactions with other parts of the binding sites on crystal structure. These ligands were prepared by following the appropriate procedures and in silico molecular docking analysis were per- formed to by a FleX X tool. 3,4-Dihydroxyphenyl acetic acid and epicatechin had the highest binding energy with hydrogen bonding to crucial SER530 and TYR385 amino acid residues of COX-2. Gallic acid and epicatechin are promising lead compounds for LOX-3 inhibition with a binding pose depicting hydrogen bonding to ASP766, GLN716 and GLN514 were encouraging. In vivo enzyme inhibition studies recorded microgram/mL for 3,4-dihydroxyphe- nyl acetic acid and epicatechin for inhibiting COX-2 were 28 and 35.25 mi- crogram/mL respectively in comparison to diclofenac with 1.3 microgram/ mL (p ≤ 0.05). Gallic acid and epicatechin inhibited LOX-3 with IC50 of 25 and 42 microgram/mL respectively in comparison to diclofenac with 1.5 micro- gram/mL (p ≤ 0.05). Conclusion: The current data supports the presence of potent bioactives naturally and conclusive proof could be provided by further clinical studies.