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Mapping myeloperoxidase to identify its promiscuity properties using docking and molecular dynamics simulations
L A Ramírez-Durán1, M C Rosales-Hernández, Maricarmen Hernández-Rodríguez
1Laboratorio de Biofísica y Biocatálisis, Sección de Estudios de Posgrado e Investigación de la Escuela Superior de Medicina del Instituto Politécnico Nacional Plan de San Luis y Díaz Mirón s/n, C.P. 11340 México, DF.
Abstract:
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.
Insights
Myeloperoxidase (MPO) inhibitors bind to a single principal binding site (PBS) on the MPO enzyme. This site
Area of Science:
- Biochemistry and Molecular Biology
- Pharmacology and Drug Discovery
Background:
- Myeloperoxidase (MPO) is a key enzyme in neutrophils, producing hypochlorous acid (HOCl).
- Elevated MPO and HOCl levels are implicated in various diseases, making MPO inhibitors (MPOis) a therapeutic target.
- The molecular recognition properties and binding site(s) of MPOis are not fully understood, limiting drug development.
Purpose of the Study:
- To elucidate the molecular recognition properties of MPO inhibitors.
- To investigate whether MPO possesses a single or multiple binding sites for aryl compounds.
- To understand the structural basis for MPO's promiscuity with different ligands.
Main Methods:
- Docking simulations were employed to analyze MPO binding site recognition.
- X-ray structures and molecular dynamics (MD) simulation snapshots were used to model MPO-ligand interactions.
- Q-Site Finder was utilized to identify potential binding sites on the MPO enzyme.
Main Results:
- All evaluated aryl ligands, including MPO inhibitors and tyrosine, bind to the same site, termed the 'principal binding site' (PBS).
- The PBS is characterized by an aromatic cluster (F99, F366, F407) and a heme group, mediating ligand recognition via π-π interactions.
- Limited conformational variations were observed in MPO, with minor side-chain movements accommodating different ligand interactions based on chemical structure.
Conclusions:
- MPO exhibits high promiscuity due to a single principal binding site that accommodates diverse ligands through specific interactions.
- Hydrazides, exemplified by ABAH, demonstrate consistent binding interactions, suggesting their potential as effective MPO inhibitors.
- Understanding the MPO binding site and ligand interactions is crucial for designing targeted MPOis for disease treatment.
