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Discovery of Novel Pim-1 Kinase Inhibitors by a Hierarchical Multistage Virtual Screening Approach Based on SVM Model, Pharmacophore, and Molecular Docking.

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Title: Discovery of Novel Pim-1 Kinase Inhibitors by a Hierarchical Multistage Virtual Screening Approach Based on SVM Model, Pharmacophore, and Molecular Docking.
Authors: Ji-Xia Ren1, Lin-Li Li1, Ren-Lin Zheng1, Huan-Zhang Xie1, Zhi-Xing Cao1, Shan Feng1, You-Li Pan1, Xin Chen1, Yu-Quan Wei1, Sheng-Yong Yang1
Source: Journal of Chemical Information & Modeling. Jun2011, Vol. 51 Issue 6, p1364-1375. 12p.
Subjects: Enzyme inhibitors, Proto-oncogenes, Protein kinases, Support vector machines, Chemical libraries, Enamines
Abstract: In this investigation, we describe the discovery of novel potent Pim-1 inhibitors by employing a proposed hierarchical multistage virtual screening (VS) approach, which is based on support vector machine-based (SVM-based VS or SB-VS), pharmacophore-based VS (PB-VS), and docking-based VS (DB-VS) methods. In this approach, the three VS methods are applied in an increasing order of complexity so that the first filter (SB-VS) is fast and simple, while successive ones (PB-VS and DB-VS) are more time-consuming but are applied only to a small subset of the entire database. Evaluation of this approach indicates that it can be used to screen a large chemical library rapidly with a high hit rate and a high enrichment factor. This approach was then applied to screen several large chemical libraries, including PubChem, Specs, and Enamine as well as an in-house database. From the final hits, 47 compounds were selected for further in vitro Pim-1 inhibitory assay, and 15 compounds show nanomolar level or low micromolar inhibition potency against Pim-1. In particular, four of them were found to have new scaffolds which have potential for the chemical development of Pim-1 inhibitors. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Chemical Information & Modeling is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Chemical+Information+%26+Modeling%22">Journal of Chemical Information & Modeling</searchLink>. Jun2011, Vol. 51 Issue 6, p1364-1375. 12p.
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  Data: <searchLink fieldCode="DE" term="%22Enzyme+inhibitors%22">Enzyme inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Proto-oncogenes%22">Proto-oncogenes</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+kinases%22">Protein kinases</searchLink><br /><searchLink fieldCode="DE" term="%22Support+vector+machines%22">Support vector machines</searchLink><br /><searchLink fieldCode="DE" term="%22Chemical+libraries%22">Chemical libraries</searchLink><br /><searchLink fieldCode="DE" term="%22Enamines%22">Enamines</searchLink>
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  Data: In this investigation, we describe the discovery of novel potent Pim-1 inhibitors by employing a proposed hierarchical multistage virtual screening (VS) approach, which is based on support vector machine-based (SVM-based VS or SB-VS), pharmacophore-based VS (PB-VS), and docking-based VS (DB-VS) methods. In this approach, the three VS methods are applied in an increasing order of complexity so that the first filter (SB-VS) is fast and simple, while successive ones (PB-VS and DB-VS) are more time-consuming but are applied only to a small subset of the entire database. Evaluation of this approach indicates that it can be used to screen a large chemical library rapidly with a high hit rate and a high enrichment factor. This approach was then applied to screen several large chemical libraries, including PubChem, Specs, and Enamine as well as an in-house database. From the final hits, 47 compounds were selected for further in vitro Pim-1 inhibitory assay, and 15 compounds show nanomolar level or low micromolar inhibition potency against Pim-1. In particular, four of them were found to have new scaffolds which have potential for the chemical development of Pim-1 inhibitors. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Journal of Chemical Information & Modeling is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1021/ci100464b
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      – TitleFull: Discovery of Novel Pim-1 Kinase Inhibitors by a Hierarchical Multistage Virtual Screening Approach Based on SVM Model, Pharmacophore, and Molecular Docking.
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              Text: Jun2011
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