title: Aldose reductase from Schistosoma japonicum: crystallization and structure-based inhibitor screening for discovering antischistosomal lead compounds.
abstract: BACKGROUND
  Schistosomiasis is a neglected tropical disease with high morbidity and mortality in the world. Currently, the treatment of this disease depends almost exclusively on praziquantel (PZQ); however, the emergence of drug resistance to PZQ in schistosomes makes the development of novel drugs an urgent task. Aldose reductase (AR), an important component that may be involved in the schistosome antioxidant defense system, is predicted as a potential drug target.
  
  
  METHODS
  The tertiary structure of Schistosoma japonicum AR (SjAR) was obtained through X-ray diffraction method and then its potential inhibitors were identified from the Maybridge HitFinder library by virtual screening based on this structural model. The effects of these identified compounds on cultured adult worms were evaluated by observing mobility, morphological changes and mortality. To verify that SjAR was indeed the target of these identified compounds, their effects on recombinant SjAR (rSjAR) enzymatic activity were assessed. The cytotoxicity analysis was performed with three types of human cell lines using a Cell Counting Kit-8.
  
  
  RESULTS
  We firstly resolved the SjAR structure and identified 10 potential inhibitors based on this structural model. Further in vitro experiments showed that one of the compounds, renamed as AR9, exhibited significant inhibition in the activity of cultured worms as well as inhibition of enzymatic activity of rSjAR protein. Cytotoxicity analysis revealed that AR9 had relatively low toxicity towards host cells.
  
  
  CONCLUSIONS
  The work presented here bridges the gap between virtual screening and experimental validation, providing an effective and economical strategy for the development of new anti-parasitic drugs. Additionally, this study also found that AR9 may become a new potential lead compound for developing novel antischistosomal drugs against parasite AR.
authors.affiliation: Key Laboratory of Parasite and Vector Biology of MOH, Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, 207 Rui-Jin Road II, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: David H
authors.initials: DH
authors.lastname: Dyer
authors.forename: Jingdong
authors.initials: J
authors.lastname: Cheng
authors.forename: Jipeng
authors.initials: J
authors.lastname: Wang
authors.forename: Shuqi
authors.initials: S
authors.lastname: Wang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yang
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
mesh_terms: D000449:Aldehyde Reductase / Q000737:chemistry*; D000818:Animals; D000871:Anthelmintics / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D001681:Biological Assay; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D015801:Helminth Proteins / Q000737:chemistry*; D008124:Locomotion / Q000187:drug effects; D011487:Protein Conformation; D012549:Schistosoma japonicum / Q000033:anatomy & histology / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D016019:Survival Analysis
chemical_list: D000871:Anthelmintics; D004791:Enzyme Inhibitors; D015801:Helminth Proteins; D000449:Aldehyde Reductase