title: Identification of Novel Structurally Diverse Anaplastic Lymphoma Kinase Inhibitors Based on Pharmacophore Modeling, Virtual Screening and Molecular Docking.
abstract: OBJECTIVE
  Anaplastic lymphoma kinase, an insulin receptor protein-tyrosine kinase, is a very attractive receptor protein target for anticancer therapy. This study was undertaken to identify novel structurally diverse anaplastic lymphoma kinase inhibitors.
  
  
  METHODS
  Pharmacophore hypotheses modeling, virtual screening and molecular docking were used to detect potential inhibitors of anaplastic lymphoma kinase in this paper.
  
  
  RESULTS
  After the generation of ten pharmacophore hypotheses, Hypo1 with the highest correlation value (0.981), lowest RMS (0.565), highest cost difference (83.850) along with four typical chemical features was regarded as the best hypothesis. Hypo1 contains a hydrogen bond acceptor, a hydrogen bong donor, a hydrophobic and a ring aromatic feature. And then, hypo1 was validated and used to screen three databases after screened by Lipinski's rule of five. 3015 hits screened by Hypo1 were submitted to molecular docking based on the crystal structure of anaplastic lymphoma kinase.
  
  
  CONCLUSIONS
  all the seven molecules formed hydrogen bond interaction with Met1199 as well as formed several other hydrogen bond interactions with different residues. All of them formed Van Der Waals interaction with hydrophobic pocket which made up of residues of Ala1148, Leu1256, Leu1196, Leu1198 Val1130 and Val1180. Some of them also formed van der Waals interaction in somewhere else of protein pocket.
authors.forename: Rong
authors.initials: R
authors.lastname: You
authors.affiliation: College of Chemical Engineering, Sichuan University, Sichuan, Chengdu, 610065, China. zhoulu@scu.edu.cn.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.forename: Liangliang
authors.initials: L
authors.lastname: Zhong
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Li
authors.forename: Suwen
authors.initials: S
authors.lastname: Zhou
authors.forename: Yahui
authors.initials: Y
authors.lastname: Tian
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000737:chemistry; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases