Different Structures—Similar Effect: Do Substituted 5-(4-Methoxyphenyl)-1H-indoles and 5-(4-Methoxyphenyl)-1H-imidazoles Represent a Common Pharmacophore for Substrate Selective Inhibition of Linoleate Oxygenase Activity of ALOX15?

Mammalian 15-lipoxygenases (ALOX15) are lipid peroxidizing enzymes that exhibit variable functionality in different cancer and inflammation models. The pathophysiological role of linoleic acid- arachidonic acid-derived ALOX15 metabolites rendered this enzyme a target for pharmacological research. Several indole imidazole derivatives inhibit the catalytic activity rabbit substrate-specific manner, but molecular basis allosteric inhibition remains unclear. Here, we attempt to define common pharmacophore, which is critical inhibition. We found substituted imidazoles induce weaker inhibitory effects when compared with derivatives. In silico docking studies dynamics simulations using dimeric model, inhibitor occupies substrate-binding pocket one monomer, whereas substrate fatty acid bound at center another monomer within dimer, indicated chemical modification core pharmacophore alters enzyme–inhibitor interactions, inducing reduced potency. our structural differences induced by binding translated hydrophobic dimerization cluster affect structures enzyme–substrate complexes. These data particular importance since may contribute elucidation putative roles derived from polyunsaturated acids mammalian pathophysiology.