title: Structure-based ensemble-QSAR model: a novel approach to the study of the EGFR tyrosine kinase and its inhibitors.
abstract: OBJECTIVE
  To develop a novel 3D-QSAR approach for study of the epidermal growth factor receptor tyrosine kinase (EGFR TK) and its inhibitors.
  
  
  METHODS
  One hundred thirty nine EGFR TK inhibitors were classified into 3 clusters. Ensemble docking of these inhibitors with 19 EGFR TK crystal structures was performed. Three protein structures that showed the best recognition of each cluster were selected based on the docking results. Then, a novel QSAR (ensemble-QSAR) building method was developed based on the ligand conformations determined by the corresponding protein structures.
  
  
  RESULTS
  Compared with the 3D-QSAR model, in which the ligand conformations were determined by a single protein structure, ensemble-QSAR exhibited higher R2 (0.87) and Q2 (0.78) values and thus appeared to be a more reliable and better predictive model. Ensemble-QSAR was also able to more accurately describe the interactions between the target and the ligands.
  
  
  CONCLUSIONS
  The novel ensemble-QSAR model built in this study outperforms the traditional 3D-QSAR model in rationality, and provides a good example of selecting suitable protein structures for docking prediction and for building structure-based QSAR using available protein structures.
authors: 1] Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China [2] Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden.
authors: Xian-qiang
authors: XQ
authors: Sun
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors: Lei
authors: L
authors: Chen
authors: 1] Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China [2] Department of Chemistry, Umeå University, S-90187 Umeå, Sweden.
authors: Yao-zong
authors: YZ
authors: Li
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors: Wei-hua
authors: WH
authors: Li
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors: Gui-xia
authors: GX
authors: Liu
authors: Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden.
authors: Yao-quan
authors: YQ
authors: Tu
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors: Yun
authors: Y
authors: Tang
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D008024:Ligands; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship
chemical_list: D008024:Ligands; D066246:ErbB Receptors