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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]
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Database: Engineering Source
Description
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]
ISSN:15499596
DOI:10.1021/ci100464b