title: Discovery of novel Pim-1 kinase inhibitors by a hierarchical multistage virtual screening approach based on SVM model, pharmacophore, and molecular docking.
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.
authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
authors: Ji-Xia
authors: JX
authors: Ren
authors: Lin-Li
authors: LL
authors: Li
authors: Ren-Lin
authors: RL
authors: Zheng
authors: Huan-Zhang
authors: HZ
authors: Xie
authors: Zhi-Xing
authors: ZX
authors: Cao
authors: Shan
authors: S
authors: Feng
authors: You-Li
authors: YL
authors: Pan
authors: Xin
authors: X
authors: Chen
authors: Yu-Quan
authors: YQ
authors: Wei
authors: Sheng-Yong
authors: SY
authors: Yang