title: Quantitative structure-activity relationship and molecular docking of artemisinin derivatives to vascular endothelial growth factor receptor 1.
abstract: OBJECTIVE
  The antimalarial drug artemisinin has been shown to exert anticancer activity through anti-angiogenic effects. For further drug development, it may be useful to have derivatives with improved anti-angiogenic properties.
  
  
  METHODS
  We performed molecular docking of 52 artemisinin derivatives to vascular endothelial growth factor receptors (VEGFR1, VEGFR2), and VEGFA ligand using Autodock4 and AutodockTools-1.5.7.rc1 using the Lamarckian genetic algorithm. Quantitative structure-activity relationship (QSAR) analyses of the compounds prepared by Corina Molecular Networks were performed using the Molecular Operating Environment MOE 2012.10.
  
  
  RESULTS
  A statistically significant inverse relationship was obtained between in silico binding energies to VEGFR1 and anti-angiogenic activity in vivo of a test-set of artemisinin derivatives (R=-0.843; p=0.035). This served as a control experiment to validate molecular docking predicting anti-angiogenc effects. Furthermore, 52 artemisinin derivatives were docked to VEGFR1 and in selected examples also to VEGFR2 and VEGFA. Higher binding affinities were calculated for receptors than for the ligand. The best binding affinities to VEGFR1 were found for an artemisinin dimer, 10-dihydroartemisinyl-2-propylpentanoate, and dihydroartemisinin α-hemisuccinate sodium salt. QSAR analyses revealed significant relationships between VEGFR1 binding energies and defined molecular descriptors of 35 artemisinins assigned to the training set (R=0.0848, p<0.0001) and 17 derivatives assigned to the test set (R=0.761, p<0.001).
  
  
  CONCLUSIONS
  Molecular docking and QSAR calculations can be used to identify novel artemisinin derivatives with anti-angiogenic effects.
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors: Mohamed E M
authors: ME
authors: Saeed
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors: Onat
authors: O
authors: Kadioglu
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors: Ean-Jeong
authors: EJ
authors: Seo
authors: Biomedical Sciences Institute Abel Salazar, University of Porto, Porto, Portugal Heidelberg School of Chinese Medicine, Heidelberg, Germany.
authors: Henry Johannes
authors: HJ
authors: Greten
authors: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors: Ruth
authors: R
authors: Brenk
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany Efferth@uni-mainz.de.
authors: Thomas
authors: T
authors: Efferth
mesh_terms: D037621:Artemisinins / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry
chemical_list: D037621:Artemisinins; D008024:Ligands; D042461:Vascular Endothelial Growth Factor A; C031327:artemisinin; C000588866:KDR protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Artemisia annua; QSAR; artemisinin; cancer; molecular docking; quantitative structure-activity relationship calculations; vascular endothelial growth factor receptor