Molecular modeling study of 2-substituted isoindoline derivatives of α-amino acids as inhibitors of lipoxygenase by docking simulations

In this work two series of isoindolines 1(a-g) and 2(a-g) were evaluated as possible inhibitors of lipoxygenase (LOX) by docking studies, as well as for the antiinflammatories isoindolilamides 3-5 and ibuprofen 6, as part of a theoretical study to found dual LOX/COX inhibitory activities. Therefore, dihydrodimethylbenzofurane 7, licofelone 8 and darbufelone 9 were also evaluated, which are wellknown as dual LOX/COX inhibitors and consequently, in this work they were used to identify their binding sites on the LOX and compared with those obtained from 1(a-g), 2(a-g) and 3 to 6 under study. Analysis of the results showed that all compounds under study could inhibit to the LOX, since they are binding in the same or close to the region as the compounds 7-9 taken as references. Several interactions of heteroatom of all compounds with the amino acid residues of binding sites of LOX were determined. The ΔG values were obtained for all the complexes (LOX-compound), among all the complexes, LOX-8 (-12.76 kcal/mol) resulted to be the most stable; and from the compounds under study, LOX-1f (-8.97 kcal/mol) resulted to be more stable than the other compounds tested. Whereas, theoretical dissociation constant values K _d (μM) were obtained. Among all compounds, 8 (0.000433 μM) showed more affinity to LOX; while from compounds under study, 1f (0.266 μM) exhibited more affinity to LOX. These results also show that compounds 1(a-g) and 2(a-g), and 3-6 could have a dual LOX/COX/inhibition, as have been shown for 7-9 and from their similar docking study within the COX-1 and COX-2 previously reported.