Abstract
There is an increasing interest in developing novel eosinophil peroxidase (EPO) inhibitors, in order to provide new treatment strategies against chronic inflammatory and neurodegenerative diseases caused by eosinophilic disorder. Within this study, a ligand-based pharmacophore model for EPO inhibitors was generated and used for in silico screening of large 3 D molecular structure databases, containing more than 4 million compounds. Hits obtained were clustered and a total of 277 compounds were selected for biological assessment. A class of 2-(phenyl)amino-aceto-hydrazides with different substitution pattern on the aromatic ring was found to contain the most potent EPO inhibitors, exhibiting IC50 values down to 10 nM. The generated pharmacophore model therefore, represents a valuable tool for the selection of compounds for biological testing. The compounds identified as potent EPO inhibitors will serve to initiate a hit to lead and lead optimisation program for the development of new therapeutics against eosinophilic disorders.
Highlights
Eosinophil peroxidase (EPO), a member of the peroxidase-cyclooxygenase superfamily[1] is a fundamental component of the leukocytes granule – the eosinophils that are specialised human phagocytes with critical role in eliminating tissue-invasive large parasites
Our stated goal is to develop potent inhibitors against EPO in order to provide new treatment strategies against chronic inflammatory and neurodegenerative diseases caused by eosinophilic disorder
This study provides a series of EPO-inhibiting 2-(phenyl)amino-acetohydrazides[26] as candidates for further biological investigations and lead optimisation
Summary
Eosinophil peroxidase (EPO), a member of the peroxidase-cyclooxygenase superfamily[1] is a fundamental component of the leukocytes granule – the eosinophils that are specialised human phagocytes with critical role in eliminating tissue-invasive large parasites. In the case of eosinophilic disorders and accumulation of eosinophils in various organs EPO contributes to chronic inflammatory[5–8] and neurodegenerative diseases[9]. Most eosinophils are found in the connective tissue immediately beneath the epithelium of the gut, urogenital and respiratory tract At this location they release diverse biologically active molecules, like EPO, cytokines, chemokines and membrane-derived mediators[12]. Very recently it was shown that EPO-generated oxidants mediated mucus plugs formation in patients with asthma linked to eosinophilia and airflow obstruction[17]. Eosinophils can accumulate in regions where body’s own tissue or cells are misguided and respectively shows malfunction: in the case of endometriosis, eosinophils, primarily the main granule protein EPO is suspected of contributing to the chronic inflammatory processes of endometriosis[19].
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