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MPO Inhibitors Selected by Virtual Screening
Author(s) -
Malvezzi Alberto,
Queiroz Raphael F,
de Rezende Leandro,
Augusto Ohara,
Amaral Antonia T.do
Publication year - 2011
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201100016
Subject(s) - pharmacophore , myeloperoxidase , virtual screening , docking (animal) , chemistry , hydrazide , drug discovery , combinatorial chemistry , enzyme , protein data bank (rcsb pdb) , biochemistry , pharmacology , computational biology , stereochemistry , biology , inflammation , medicine , immunology , organic chemistry , nursing
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 IC 50 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.