WISDOM-II: Screening against multiple targets implicated in malaria using computational grid infrastructures
| Autor: | Colin Peter Kenyon, Vinod Kasam, Giulio Rastelli, Doman Kim, Astrid Maass, Marli Botha, Ana Dacosta, Gianluca Degliesposti, Martin Hofmann-Apitius, Jean Salzemann, Raúl Isea, Vincent Breton |
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| Přispěvatelé: | Laboratoire de Physique Corpusculaire - Clermont-Ferrand (LPC), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Department of Bioinformatics [Sankt Augustin] (Fraunhofer SCAI), Fraunhofer Institute for Algorithms and Scientific Computing (Fraunhofer SCAI), Fraunhofer (Fraunhofer-Gesellschaft)-Fraunhofer (Fraunhofer-Gesellschaft), WISDOM, Publica |
| Rok vydání: | 2009 |
| Předmět: |
lcsh:Arctic medicine. Tropical medicine
lcsh:RC955-962 drug design In silico RC955-962 Embarrassingly parallel Protozoan Proteins malaria Plasmepsin RC109-216 Infectious and parasitic diseases Computational biology Biology Ligands 010402 general chemistry Bioinformatics grid 01 natural sciences lcsh:Infectious and parasitic diseases 03 medical and health sciences Drug Delivery Systems Arctic medicine. Tropical medicine Humans lcsh:RC109-216 virtual screening Glutathione Transferase 030304 developmental biology 0303 health sciences Virtual screening Drug discovery Research Computational Biology Matrix Attachment Regions Grid [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] 3. Good health 0104 chemical sciences Tetrahydrofolate Dehydrogenase WISDOM Infectious Diseases Pharmaceutical Preparations Drug development Docking (molecular) Drug Design Parasitology [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] Medical Informatics Protein Binding |
| Zdroj: | Malaria Journal Malaria Journal, BioMed Central, 2009, 8, pp.88. ⟨10.1186/1475-2875-8-88⟩ Malaria Journal, 2009, 8, pp.88. ⟨10.1186/1475-2875-8-88⟩ Fraunhofer SCAI Malaria Journal, Vol 8, Iss 1, p 88 (2009) OpenAIRE DOAJ-Articles Archivio istituzionale della ricerca-Università di Modena e Reggio Emilia Europe PubMed Central Fraunhofer-ePrints |
| ISSN: | 1475-2875 |
| DOI: | 10.1186/1475-2875-8-88 |
| Popis: | 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. Motivation 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. Conclusion 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. |
| Databáze: | OpenAIRE |
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