Mapping myeloperoxidase to identify its promiscuity properties using docking and molecular dynamics simulations.

Myeloperoxidase (MPO) is the most abundant heme protein in neutrophils, and MPO catalyzes hypochlorous acid (HOCl) formation. MPO inhibitors (MPOis) can be used to treat several diseases in which MPO and HOCl levels are elevated. The molecular details of several MPOis have not been extensively studied to elucidate their molecular recognition properties. In addition, it is not known whether MPO has only one binding site or more binding sites for aryl compounds, which would explain its promiscuity properties. Therefore, docking simulations were performed to analyze the MPO binding site recognition using several X-ray structures and snapshots retrieved from molecular dynamics (MD) simulations to simulate the binding of MPO with several known aryl ligands. All of the evaluated ligands were recognized by MPO at the same site, which was identified by the Q-Site Finder as being one of the principal sites and named herein as the "principal binding site" (PBS). The PBS is composed of Q91, H95, F99, R239, E242, F366 and F407. The results indicate that the MPO ligand recognition is mediated by π-π interactions with an aromatic cluster (F99, F366, F407 and a heme group), giving rise to high MPO promiscuity. In addition, MD simulations and X-ray crystallography show limited conformational variations in the MPO. In addition, either MPOis or another substrate (tyrosine) reaches the same site, but different interactions were observed. Therefore, the results indicate minor movement in the side chain of the mentioned amino acids that allow ligands to be recognized in the same MPO site with different interactions that are dependent on their chemical structures. Furthermore, docking study samples of several conformations retrieved from the MD simulations showed that ABAH was one of the ligands that always had the same interaction. This result provides potential evidence for hydrazides being very good MPOis.