title: MPO Inhibitors Selected by Virtual Screening.
abstract: The hemeprotein myeloperoxidase (MPO) participates in innate immune defense through its ability to generate potent microbicidal oxidants. However, these oxidants are also key mediators of the tissue damage associated with many inflammatory diseases. Thus, there is considerable interest in developing therapeutically useful MPO inhibitors. Here, we used structure-based drug design (SBDD) and ligand-based drug design (LBDD) to select for potentially new and selective MPO inhibitors. A pharmacophore model was developed based on the crystal structure of human MPO in complex with salicylhydroxamic acid (SHA), a known inhibitor of the enzyme. The pharmacophore model was used to screen the ZINC database for potential ligands, which were further filtered on the basis of their physical-chemical properties and docking score. The filtered compounds were visually inspected, and nine were purchased for experimental studies. Surprisingly, almost all of the selected compounds belonged to the aromatic hydrazide class, which had been previously described as MPO inhibitors. The compounds selected by virtual screening were shown to inhibit the chlorinating activity of MPO; the top four compounds displayed IC50 values ranging from 1.0 to 2.8 µM. MPO inactivation by the most effective compound was shown to be irreversible. Overall, our results show that SBDD and LBDD may be useful for the rational development of new MPO inhibitors.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo-SP, 05513-970, Brazil.|Departamento Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo-SP, 05513-970, Brazil phone: +5511 3091 3846.
authors.forename: Alberto
authors.initials: A
authors.lastname: Malvezzi
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo-SP, 05513-970, Brazil.
authors.forename: Raphael F
authors.initials: RF
authors.lastname: Queiroz
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo-SP, 05513-970, Brazil.|Departamento Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo-SP, 05513-970, Brazil phone: +5511 3091 3846.
authors.forename: Leandro
authors.initials: L
authors.lastname: de Rezende
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo-SP, 05513-970, Brazil.
authors.forename: Ohara
authors.initials: O
authors.lastname: Augusto
authors.affiliation: Departamento Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo-SP, 05513-970, Brazil phone: +5511 3091 3846. atdamara@iq.usp.br.
authors.forename: Antonia T-do
authors.initials: AT
authors.lastname: Amaral
keywords: Aromatic hydrazides; Docking; Myeloperoxidase inhibitors; Pharmacophore; Virtual screening