SHAFTS: A Hybrid Approach for 3D Molecular Similarity Calculation. 2. Prospective Case Study in the Discovery of Diverse p90 Ribosomal S6 Protein Kinase 2 Inhibitors To Suppress Cell Migration

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• 作者：Weiqiang Lu ; Xiaofeng Liu ; Xianwen Cao ; Mengzhu Xue ; Kangdong Liu ; Zhenjiang Zhao ; Xu Shen ; Hualiang Jiang ; Yufang Xu ; Jin Huang ; Honglin Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：May 26, 2011
• 年：2011
• 卷：54
• 期：10
• 页码：3564-3574
• 全文大小：1058K
• 年卷期：v.54,no.10(May 26, 2011)
• ISSN：1520-4804

文摘

We described a prospective application of ligand-based virtual screening program SHAFTS to discover novel inhibitors for p90 ribosomal S6 protein kinase 2 (RSK2). Taking the putative 3D conformations of two weakly binding RSK2 NTKD inhibitors as query templates, SHAFTS was used to perform 3D similarity based virtual screening because of a lack of crystal structure of RSK2 protein, thus leading to the identification of several novel scaffolds that would have been missed by conventional 2D fingerprint methods. The most potent hit compounds show low micromolar inhibitory activities against RSK2. In particular, one of the hit compounds exhibits potent antimigration activity against the MDA-MB-231 tumor cell. The results exemplified SHAFTS鈥?application in active enrichment and scaffold hopping, which is of general interest for lead identification in drug discovery endeavors and also provides novel scaffolds that lay the foundation for uncovering new RSK2 regulatory mechanisms.