title: WISDOM-II: screening against multiple targets implicated in malaria using computational grid infrastructures.
abstract: BACKGROUND
  Despite continuous efforts of the international community to reduce the impact of malaria on developing countries, no significant progress has been made in the recent years and the discovery of new drugs is more than ever needed. Out of the many proteins involved in the metabolic activities of the Plasmodium parasite, some are promising targets to carry out rational drug discovery.
  
  
  BACKGROUND
  Recent years have witnessed the emergence of grids, which are highly distributed computing infrastructures particularly well fitted for embarrassingly parallel computations like docking. In 2005, a first attempt at using grids for large-scale virtual screening focused on plasmepsins and ended up in the identification of previously unknown scaffolds, which were confirmed in vitro to be active plasmepsin inhibitors. Following this success, a second deployment took place in the fall of 2006 focussing on one well known target, dihydrofolate reductase (DHFR), and on a new promising one, glutathione-S-transferase.
  
  
  METHODS
  In silico drug design, especially vHTS is a widely and well-accepted technology in lead identification and lead optimization. This approach, therefore builds, upon the progress made in computational chemistry to achieve more accurate in silico docking and in information technology to design and operate large scale grid infrastructures.
  
  
  RESULTS
  On the computational side, a sustained infrastructure has been developed: docking at large scale, using different strategies in result analysis, storing of the results on the fly into MySQL databases and application of molecular dynamics refinement are MM-PBSA and MM-GBSA rescoring. The modeling results obtained are very promising. Based on the modeling results, In vitro results are underway for all the targets against which screening is performed.
  
  
  CONCLUSIONS
  The current paper describes the rational drug discovery activity at large scale, especially molecular docking using FlexX software on computational grids in finding hits against three different targets (PfGST, PfDHFR, PvDHFR (wild type and mutant forms) implicated in malaria. Grid-enabled virtual screening approach is proposed to produce focus compound libraries for other biological targets relevant to fight the infectious diseases of the developing world.
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), 53754 Sankt Augustin, Germany. kasam@scai.fraunhofer.de
authors.forename: Vinod
authors.initials: V
authors.lastname: Kasam
authors.forename: Jean
authors.initials: J
authors.lastname: Salzemann
authors.forename: Marli
authors.initials: M
authors.lastname: Botha
authors.forename: Ana
authors.initials: A
authors.lastname: Dacosta
authors.forename: Gianluca
authors.initials: G
authors.lastname: Degliesposti
authors.forename: Raul
authors.initials: R
authors.lastname: Isea
authors.forename: Doman
authors.initials: D
authors.lastname: Kim
authors.forename: Astrid
authors.initials: A
authors.lastname: Maass
authors.forename: Colin
authors.initials: C
authors.lastname: Kenyon
authors.forename: Giulio
authors.initials: G
authors.lastname: Rastelli
authors.forename: Martin
authors.initials: M
authors.lastname: Hofmann-Apitius
authors.forename: Vincent
authors.initials: V
authors.lastname: Breton
mesh_terms: D019295:Computational Biology / Q000379:methods*; D016503:Drug Delivery Systems; D015195:Drug Design; D005982:Glutathione Transferase; D006801:Humans; D008024:Ligands; D008288:Malaria / Q000188:drug therapy*; D045170:Matrix Attachment Regions; D008490:Medical Informatics / Q000458:organization & administration*; D004364:Pharmaceutical Preparations; D011485:Protein Binding; D015800:Protozoan Proteins; D013762:Tetrahydrofolate Dehydrogenase
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D015800:Protozoan Proteins; D013762:Tetrahydrofolate Dehydrogenase; D005982:Glutathione Transferase