How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling

Heme oxygenase-1 (HO-1) inhibition is associated with antitumor activity.Imidazole-based analogues show effective and selective inhibitory potency ofHO-1. In this work, five single-crystal structures of four imidazole-basedcompounds are presented, with an in-depth structural analysis. In order to studythe influence of the conformation of the ligands on binding to protein,conformational data from crystallography are compared with quantummechanics analysis and molecular docking studies. Molecular docking ofimidazole-based analogues in the active site of HO-1 is in good agreement withthe experimental structures. Inhibitors interact with the heme cofactor and ahydrophobic pocket (Met34, Phe37, Val50, Leu147 and Phe214) in the HO-1binding site. An alternate binding mode can be hypothesized for some inhibitorsin the series.