Related Experiment Video
Updated: Feb 27, 2026
High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure
Jalal Soubhye1, Ibaa Chikh Alard2, Iyas Aldib1
1Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles , Campus de la Plaine, Boulevard du Triomphe, 1050 Bruxelles, Belgium.
Abstract:
The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 μM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.
Insights
Researchers identified potent inhibitors for myeloperoxidase (MPO), an enzyme linked to inflammation. The best compounds, including a novel mechanism-based inhibitor, show promise for treating inflammatory diseases.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Myeloperoxidase (MPO) is a heme enzyme crucial for innate immunity but also implicated in inflammatory disease pathogenesis.
- Circulating MPO and its derived oxidants contribute to disease, driving interest in developing specific MPO inhibitors.
Purpose of the Study:
- To identify novel, efficient, and specific inhibitors of myeloperoxidase (MPO).
- To explore new virtual screening methods for drug discovery targeting MPO.
Main Methods:
- A virtual screening strategy combining ligand-based pharmacophore modeling and structure-based virtual screening was employed.
- An initial library of 727,842 compounds was screened, leading to 28 selected molecules for in vitro testing.
Main Results:
- Twelve of the 28 tested compounds exhibited IC50 values below 5 μM.
- Two compounds, 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42), showed IC50 values of 44 nM and 50 nM, respectively.
- Compound 28 was identified as the first potent, irreversible, mechanism-based MPO inhibitor at nanomolar concentrations.
Conclusions:
- The novel virtual screening approach successfully identified potent MPO inhibitors.
- Compound 28 represents a significant advancement as a mechanism-based inhibitor, offering potential therapeutic applications for MPO-related inflammatory conditions.
More Related Videos
08:31Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
10:25Screening Traditional Chinese Medicine Compounds for Inhibiting UCHL3 Activity Based on Molecular Docking and Deubiquitinating Enzyme Probe Technology
Published on: November 22, 2024
