A Multistep Computational Approach to Achieve a Complete Human 5‐Lipoxygenase Structure and Provide a Pharmacophore Model for Further Drug Design

Human 5-lipoxygenase (5-LOX) plays a crucial role in the biosynthesis of leukotrienes (LTs). Therefore, 5-LOX inhibitors are designed as effective agents for the treatment of several diseases such as asthma, cardiovascular disorders, allergies, and cancer. Insights into crystal structures of several 5-LOX isoforms have revealed that this protein adopts two different conformations (open/closed) through modulation of its Hα2 and arched helix regions, which are conditioned by the presence or absence of ligand in the active site; moreover, these structures are incomplete in regions critical for ligand binding. To advance the design of 5-LOX inhibitors, we developed a computational procedure to reconstruct the first full-length open conformation structure of 5-LOX complexed with chelating inhibitor within the active site. Dynamic simulations and protein model validation confirmed the quality of our model, which was subsequently used for docking analyses and culminated in the development of a structure-based pharmacophore model. These computational studies might constitute powerful tools for rationally designing and identifying novel 5-LOX iron chelator inhibitors.