title: Virtual screening and experimental validation of novel histone deacetylase inhibitors.
abstract: Histone deacetylases (HDACs) are promising therapeutic targets for the treatment of cancer, diabetes and other human diseases. HDAC inhibitors, as a new class of potential therapeutic agents, have attracted a great deal of interest for both research and clinical applications. Increasing efforts have been focused on the discovery of HDAC inhibitors and some HDAC inhibitors have been approved for use in cancer therapy. However, most HDAC inhibitors, including the clinically approved agents, do not selectively inhibit the deacetylase activity of class I and II HDAC isforms, and many suffer from metabolic instability. This study aims to identify new HDAC inhibitors by using a high-throughput virtual screening approach.
  
  
  
  An integration of in silico virtual screening and in vitro experimental validation was used to identify novel HDAC inhibitors from a chemical database.
  
  
  
  A virtual screening workflow for HDAC inhibitors were created by integrating ligand- and receptor- based virtual screening methods. Using the virtual screening workflow, 22 hit compounds were selected and further tested via in vitro assays. Enzyme inhibition assays showed that three of the 22 compounds had HDAC inhibitory properties. Among these three compounds, ZINC12555961 significantly inhibited HDAC activity. Further in vitro experiments indicated that ZINC12555961 can selectively inhibit proliferation and promote apoptosis of cancer cells.
  
  
  
  In summary, our study presents three new and potent HDAC inhibitors and one of these HDAC inhibitors shows anti-proliferative and apoptosis-inducing activity against various cancer cell lines. These results suggest that the developed virtual screening workflow can provide a useful source of information for the screening and validation of new HDAC inhibitors. The new-found HDAC inhibitors are worthy to further and more comprehensive investigations.
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China. huangyx356@nenu.edu.cn.
authors.forename: Yan-Xin
authors.identifier: 0000-0002-4913-8161
authors.initials: YX
authors.lastname: Huang
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China.
authors.forename: Qiu-Hang
authors.initials: QH
authors.lastname: Song
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Zheng
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Fan
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Liu
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China.
authors.forename: Yong-Li
authors.initials: YL
authors.lastname: Bao
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China.
authors.forename: Lu-Guo
authors.initials: LG
authors.lastname: Sun
authors.affiliation: School of Computer Science and Information Technology, Northeast Normal University, Changchun, 130117, China. lbzhang@nenu.edu.cn.
authors.forename: Li-Biao
authors.initials: LB
authors.lastname: Zhang
authors.affiliation: Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, ChangChun, 130117, China. liyx486@nenu.edu.cn.
authors.forename: Yu-Xin
authors.initials: YX
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000592:standards; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015203:Reproducibility of Results; D014584:User-Computer Interface
chemical_list: D056572:Histone Deacetylase Inhibitors
keywords: Apoptosis; Docking; HDAC inhibitors; Pharmacophore; Virtual screening