Isoniazid Derivatives as Potential Lipoxygenase-15 Inhibitors: In-vitro and In-silico Studies

The enzymatic oxidation of polyunsaturated fatty acids, particularly arachidonic acid, produces important lipid mediators such as leukotrienes and prostaglandins, which are critical for triggering inflammatory cascades in the body. The enzyme lipoxygenase-15 (LOX-15) plays a crucial role in the oxygenation of unsaturated fatty acids. Targeting this enzyme for inhibition is essential for diminishing inflammation and averting numerous potentially fatal diseases. Therefore, the inhibitory activity of a series of isoniazid derivatives, selected from our in-house library, was assessed against LOX-15 by employing both in vitro and in silico methods. Among the 23 compounds evaluated, 15 showed activity in vitro. Notably, compound 7 was the most effective, demonstrating an IC50 value of 1.4 +/- 0.1 mu M while the standard inhibitor, NDGA, showed an inhibition at 9.4 +/- 0.6 mu M. These compounds were found to competitively inhibit LOX-15, with Ki values ranging from 1.2-7.1 mu M. Molecular docking was utilized to investigate the intermolecular interactions among the active compounds. The thermodynamic stability of the compound 7 and NDGA in complex with LOX-15 was verified through 100 ns of molecular dynamics simulations. Post-simulation analyses involved RMSD, RMSF, RoG, free energy landscape, principal component analysis, and dynamic cross-correlation matrix. Compound 7 and NDGA had MM/GBSA binding energies of -54.14 +/- 2.55 kcal/mol and -35.24 +/- 3.23 kcal/mol, respectively. The study underscores the significant potential of isoniazid derivatives in LOX-15 inhibition and their role in managing inflammatory diseases.