title: Identification of inhibitors against p90 ribosomal S6 kinase 2 (RSK2) through structure-based virtual screening with the inhibitor-constrained refined homology model.
abstract: P90 ribosomal S6 kinase 2 (RSK2), which was shown to be overexpressed in human cancers, is a serine/threonine kinase and a potential target for cancer treatment. RSK2 comprises two terminal kinase domains (NTKD and CTKD) that can be inhibited by binding with different types of inhibitors at the ATP binding sites. In the absence of a crystal structure of RSK2, we constructed a model for the 3D structure of the RSK2 NTKD by homology modeling and stepwise constrained refinement with the reported inhibitors using a molecular docking method. Structure-based virtual screening was subsequently performed against a library containing commercially available compounds using the refined model. This resulted in the identification of seven novel RSK2 inhibitors with IC₅₀ values ranging from 2.4 to 14.45 μM.
authors: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors: Shiliang
authors: S
authors: Li
authors: Yi
authors: Y
authors: Zhou
authors: Weiqiang
authors: W
authors: Lu
authors: Ye
authors: Y
authors: Zhong
authors: Wenlong
authors: W
authors: Song
authors: Kangdong
authors: K
authors: Liu
authors: Jin
authors: J
authors: Huang
authors: Zhenjiang
authors: Z
authors: Zhao
authors: Yufang
authors: Y
authors: Xu
authors: Xiaofeng
authors: X
authors: Liu
authors: Honglin
authors: H
authors: Li
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D019295:Computational Biology / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3