title: 3-oxoacyl-ACP reductase from Schistosoma japonicum: integrated in silico-in vitro strategy for discovering antischistosomal lead compounds.
abstract: BACKGROUND
  Schistosomiasis is a disease caused by parasitic worms and more than 200 million people are infected worldwide. The emergence of resistance to the most commonly used drug, praziquantel (PZQ), makes the development of novel drugs an urgent task. 3-oxoacyl-ACP reductase (OAR), a key enzyme involved in the fatty acid synthesis pathway, has been identified as a potential drug target against many pathogenic organisms. However, no research on Schistosoma japonicum OAR (SjOAR) has been reported. The characterization of the SjOAR protein will provide new strategies for screening antischistosomal drugs that target SjOAR.
  
  
  RESULTS
  After cloning the SjOAR gene, recombinant SjOAR protein was purified and assayed for enzymatic activity. The tertiary structure of SjOAR was obtained by homology modeling and 27 inhibitor candidates were identified from 14,400 compounds through molecular docking based on the structure. All of these compounds were confirmed to be able to bind to the SjOAR protein by BIAcore analysis. Two compounds exhibited strong antischistosomal activity and inhibitory effects on the enzymatic activity of SjOAR. In contrast, these two compounds showed relatively low toxicity towards host cells.
  
  
  CONCLUSIONS
  The work presented here shows the feasibility of isolation of new antischistosomal compounds using a combination of virtual screening and experimental validation. Based on this strategy, we successfully identified 2 compounds that target SjOAR with strong antischistosomal activity but relatively low cytotoxicity to host cells.
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, China ; Key Laboratory of Parasite and Vector Biology of Ministry of Public Health, Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Dave
authors.initials: D
authors.lastname: Dyer
authors.forename: Jipeng
authors.initials: J
authors.lastname: Wang
authors.forename: Shuqi
authors.initials: S
authors.lastname: Wang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Du
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Haobing
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
mesh_terms: D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification*; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D003001:Cloning, Molecular; D003198:Computer Simulation; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017238:Genes, Helminth / Q000235:genetics; D015801:Helminth Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification; D056945:Hep G2 Cells; D006801:Humans; D007700:Kinetics; D012549:Schistosoma japonicum / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D000871:Anthelmintics; D004791:Enzyme Inhibitors; D015801:Helminth Proteins; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase