文献类型：期刊文献

英文题名：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

作者：Lu, Weiqiang[2];Liu, Xiaofeng[2];Cao, Xianwen[2];Xue, Mengzhu[2];Liu, Kangdong[1];Zhao, Zhenjiang[2];Shen, Xu[2];Jiang, Hualiang[2];Xu, Yufang[2];Huang, Jin[2];Li, Honglin[2]

机构：[1]Zhengzhou Univ, Basic Med Coll, Zhengzhou 450001, Peoples R China;[2]E China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

年份：2011

卷号：54

期号：10

起止页码：3564

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000290651800008)】；

基金：This work was supported by the Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China (Grants 20803022, 90813005, and 10979072), the Special Fund for Major State Basic Research Project (Grant 2009CB918501), the Shanghai Committee of Science and Technology (Grants 09dZ1975700 and 10431902600), the Innovation Program of Shanghai Municipal Education Commission (Grant 10ZZ41), the 863 Hi-Tech Program of China (Grant 2007AA02Z304), the 111 Project (Grant B07023), and the National S&T Major Project of China (Grants 2011ZX09307-002-03, 2009ZX09501-001, and 2009ZX09301-001). H.L. is sponsored by Shanghai Rising-Star Program (Grant 10QA1401800) and Program for New Century Excellent Talents in University. The authors appreciate Dr. Hua Xie and Linjiang Tong or the tyrosine protein kinase profile, and Zhongyu Xu for the compound purification analysis.

语种：英文

摘要：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' 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.