title: Integrated In Silico-In Vitro Discovery of Lung Cancer-related Tumor Pyruvate Kinase M2 (PKM2) Inhibitors.
abstract: BACKGROUND
  The tumor pyruvate kinase M2 (PKM2) is involved in the glycolytic pathway of lung cancer and targeting this kinase has been observed to radiosensitize non-small cell lung cancer (NSCLC).
  
  
  OBJECTIVE
  An integration of in silico virtual screening and in vitro kinase assay was described to discover novel PKM2 inhibitors from a candidate library containing >400,000 commercially available compounds.
  
  
  METHODS
  The method is a stepwise screening scheme that first used empirical strategies to fast exclude those undruggable compounds in the library and then employed molecular docking and molecular dynamics (MD)-based rescoring to identify few potential hits. Subsequently, the computational findings were substantiated using a standard kinase assay protocol.
  
  
  RESULTS
  Four compounds, i.e. nalidixic acid, indoprofen, hematoxylin and polydatin, were identified to inhibit PKM2 kinase at micromolar level, with IC50 values of 53, 21, 340 and 128 .M, respectively.
  
  
  CONCLUSIONS
  Structural analysis revealed that hydrogen bonds, salt bridges, π-π stacking and hydrophobic forces co-confer high stability and strong specificity to PKM2-inhibitor binding.
authors.forename: Xiangyun
authors.initials: X
authors.lastname: Ye
authors.forename: Yinjia
authors.initials: Y
authors.lastname: Sun
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Xu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 Huaihai West Road, Shanghai 200030, China. shun_lu@126.com.
authors.forename: Shun
authors.initials: S
authors.lastname: Lu
mesh_terms: D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020134:Catalytic Domain; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods; D057075:Enzyme Assays; D005960:Glucosides / Q000737:chemistry; D006416:Hematoxylin / Q000737:chemistry; D006801:Humans; D007216:Indoprofen / Q000737:chemistry; D008175:Lung Neoplasms; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009268:Nalidixic Acid / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013267:Stilbenes / Q000737:chemistry; D013963:Thyroid Hormones / Q000737:chemistry; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D005960:Glucosides; D006416:Hematoxylin; D007216:Indoprofen; D008565:Membrane Proteins; D009268:Nalidixic Acid; D047428:Protein Kinase Inhibitors; D011770:Pyruvate Kinase; D013267:Stilbenes; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C058229:polydatin