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

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Identification of Potentially Potent Heme Oxygenase 1 Inhibitors through 3D‐QSAR Coupled to Scaffold‐Hopping Analysis
ChemMedChem ( IF 3.6 ) Pub Date : 2018-05-29 , DOI: 10.1002/cmdc.201800176
Giuseppe Floresta _{1,

2} , Emanuele Amata ₁ , Maria Dichiara ₁ , Agostino Marrazzo ₁ , Loredana Salerno ₁ , Giuseppe Romeo ₁ , Orazio Prezzavento ₁ , Valeria Pittalà ₁ , Antonio Rescifina ₁

Affiliation

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.

中文翻译：

通过3D-QSAR耦合支架-跳频分析鉴定潜在的潜在血红素加氧酶1抑制剂

建立了预测血红素加氧酶1（HO-1）抑制剂活性的3D定量结构-活性关系（3D-QSAR）模型，旨在为鉴定，设计和优化新型HO-1提供有用的工具抑制剂。该模型是使用从血红素加氧酶数据库（HemeOxDB）中回收的222种HO-1抑制剂建立的，并使用Forge软件进行开发。本模型显示出很高的统计质量，这一点已被其强大的预测潜力和令人满意的描述能力所证实。绘制的3D贴图可快速直观地了解与HO-1抑制剂相互作用的静电，疏水和定型特征。通过脚手架跳频分析进行了一种新的先导化合物生成的理论方法。首次，报告了针对该目标的3D-QSAR模型，并使用许多化学上不同的HO-1抑制剂建立了该模型。该模型还很好地说明了各个配体的亲和力。新模型包含迄今已发布的对选定靶标具有高效力的所有抑制剂，并包含HO-1结合腔的完整药效基团描述。这些功能将确保在加速新的有效和选择性HO-1抑制剂的鉴定中的应用。

更新日期：2018-05-29

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