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.

Role of Neutrophils in the Pathogenesis of Nonalcoholic Steatohepatitis

“…MPO has also been studied as a target of anti-neutrophil therapies because it mediates multiple steps in neutrophil-induced inflammation and tissue damage (207). It has been attempted to inhibit the activity of MPO using chemicals that block the active site of MPO, remove MPO from the chlorination reactions, or scavenge HOCl; however, whether these strategies are valid for the treatment of NASH in experimental animal models remain unknown (208)(209)(210)(211)(212)(213)(214). The therapeutic potential of LCN2 inhibition has been examined for the treatment of various diseases, including cancer (215,216), which has led to the investigation of biological therapeutics such as monoclonal antibodies, RNA interference technology, and nanoparticle-based LCN2 modulators (158,161,(217)(218)(219).…”

Busca Virtual De Compostos Bioativos: Conceitos E Aplicações

“…124 Na literatura são encontrados vários exemplos de sucesso do uso de modelos farmacofóricos na busca virtual, permitindo identificar compostos ativos frente a diferentes alvos biológicos. [127][128][129] Além dos compostos selecionados apresentarem atividade frente ao alvo de interesse, alguns deles têm características estruturais bastante diferentes daquelas observadas nos compostos usados para construir os modelos.…”

“…Assim, na busca virtual usando diferentes filtros de seleção de modo sequencial, o filtro de ancoramento deveria ser utilizado por último, quando o número de compostos já foi significativamente reduzido. 127…”

Be Aware of Aggregators in the Search for Potential Human ecto-5′-Nucleotidase Inhibitors

“…Virtual screening (VS) and high-throughput screening (HTS) approaches have been well established as the main techniques for identification of bioactive compounds as potential drug candidates from large chemical libraries [ 1 , 2 , 3 , 4 ], showing significant success rates. However, currently it is well recognized that many screened hits are further recognized as not truly actives against their specific biological targets [ 5 , 6 , 7 , 8 ].…”