ChemMedChem
ChemMedChem
5 years ago

Heme Oxygenase Database (HemeOxDB) and QSAR Analysis of Isoform 1 Inhibitors

Heme Oxygenase Database (HemeOxDB) and QSAR Analysis of Isoform 1 Inhibitors
Giuseppe Romeo, Maria N. Modica, Orazio Prezzavento, Loredana Salerno, Giovanni Nastasi, Valeria Pittalà, Antonio Rescifina, Agostino Marrazzo, Maria Dichiara, Emanuele Amata
Due to increasing interest in the field of heme oxygenases (HOs), we built a ligand database called HemeOxDB that includes the entire set of known HO-1 and HO-2 inhibitors, resulting in more than 400 compounds. The HemeOxDB is available online at http://www.researchdsf.unict.it/hemeoxdb/, and having a robust search engine allows end users to build complex queries, sort tabulated results, and generate color-coded two- and three-dimensional graphs. This database will grow to be a tool for the design of potent and selective HO-1 or HO-2 inhibitors. We were also interested in virtually searching for alternative inhibitors, and, for the first time in the field of HOs, a quantitative structure–activity relationship (QSAR) model was built using half-maximal inhibitory concentration (IC50) values of the whole set of known HO-1 inhibitors, taken from the HemeOxDB and employing the Monte Carlo technique. The statistical quality suggested that the model is robust and possesses desirable predictive potential. The screening of US Food and Drug Administration (FDA)-approved drugs, external to our dataset, suggested new predicted inhibitors, opening the way for replacing imidazole groups. The HemeOxDB and the QSAR model reported herein may help in prospectively identifying or repurposing new drugs with optimal structural attributes for HO enzyme inhibition. Heme oxygenase inhibitors: A collection of the whole set of heme oxygenase (HO) inhibitors is reported, and inhibitors of heme oxygenase-1 (HO-1) were used in creating a Monte Carlo based QSAR model. The screening of a number of FDA-approved drugs with the developed model revealed that top-scored compounds share common sulfonylurea or sulfonyl acetamide functions, which may be novel replacements for the imidazole used in the vast majority of HO-1 inhibitors.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cmdc.201700321

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