A 3D quantitative structure–activity relationship (3D-QSAR) model for predicting the activity of heme oxygenase 1 (HO-1) inhibitors was constructed with the aim of providing a useful tool for the identification, design, and optimization of novel HO-1 inhibitors. The model was built using a set of 222 HO-1 inhibitors recovered from the Heme Oxygenase Database (HemeOxDB) and developed with the software Forge. The present model showed high statistical quality, as confirmed by its robust predictive potential and satisfactory descriptive capability. The drawn-up 3D map enables prompt visual comprehension of the electrostatic, hydrophobic, and shaping features underlying the interactions with HO-1 inhibitors. A theoretical approach for the generation of new lead compounds was performed by means of scaffold-hopping analysis. For the first time, a 3D-QSAR model is reported for this target, and was built with a number of chemically diverse HO-1 inhibitors; the model also accounts well for individual ligand affinities. The new model contains all of the inhibitors published to date with high potency toward the selected target and contains a complete pharmacophore description of the binding cavity of HO-1. These features will ensure application in accelerating the identification of new potent and selective HO-1 inhibitors.

Identification of Potentially Potent Heme Oxygenase 1 Inhibitors through 3D-QSAR Coupled to Scaffold-Hopping Analysis

Floresta Giuseppe
;
Amata Emanuele;Dichiara Maria;Marrazzo Agostino;Salerno Loredana;Romeo Giuseppe;Prezzavento Orazio;Pittalà Valeria;Rescifina Antonio
2018

Abstract

A 3D quantitative structure–activity relationship (3D-QSAR) model for predicting the activity of heme oxygenase 1 (HO-1) inhibitors was constructed with the aim of providing a useful tool for the identification, design, and optimization of novel HO-1 inhibitors. The model was built using a set of 222 HO-1 inhibitors recovered from the Heme Oxygenase Database (HemeOxDB) and developed with the software Forge. The present model showed high statistical quality, as confirmed by its robust predictive potential and satisfactory descriptive capability. The drawn-up 3D map enables prompt visual comprehension of the electrostatic, hydrophobic, and shaping features underlying the interactions with HO-1 inhibitors. A theoretical approach for the generation of new lead compounds was performed by means of scaffold-hopping analysis. For the first time, a 3D-QSAR model is reported for this target, and was built with a number of chemically diverse HO-1 inhibitors; the model also accounts well for individual ligand affinities. The new model contains all of the inhibitors published to date with high potency toward the selected target and contains a complete pharmacophore description of the binding cavity of HO-1. These features will ensure application in accelerating the identification of new potent and selective HO-1 inhibitors.
3D-QSAR; heme oxygenase; HO-1 inhibitors; scaffold hopping; virtual screening; Molecular Medicine; Pharmacology, Toxicology and Pharmaceutics (all); Organic Chemistry
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/331858
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