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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
WISDOM-II: Screening against multiple targets implicated in malaria using computational grid infrastructures
Malaria Journal, Volume 8, No. 1, Article 88, Year 2009
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Description
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. © 2009 Kasam et al; licensee BioMed Central Ltd.
Authors & Co-Authors
Kasam, Vinod
Germany, Sankt Augustin
Fraunhofer Institute for Algorithms and Scientific Computing Scai
France, Aubiere
Laboratoire de Physique de Clermont
Salzemann, Jean
France, Aubiere
Laboratoire de Physique de Clermont
Botha, Marli
South Africa, Johannesburg
Csir Biosciences
Dacosta, Ana
France, Aubiere
Laboratoire de Physique de Clermont
Degliesposti, Gianluca
Italy, Modena
Università Degli Studi Di Modena e Reggio Emilia
Isea, Raul
Venezuela, Baruta
Fundación Idea
Kim, Doman
South Korea, Gwangju
Chonnam National University
Maaß, Astrid
Germany, Sankt Augustin
Fraunhofer Institute for Algorithms and Scientific Computing Scai
Kenyon, Colin P.
South Africa, Johannesburg
Csir Biosciences
Rastelli, Giulio
Italy, Modena
Università Degli Studi Di Modena e Reggio Emilia
Hofmann-Apitius, Martin
Germany, Sankt Augustin
Fraunhofer Institute for Algorithms and Scientific Computing Scai
Breton, Vincent
France, Aubiere
Laboratoire de Physique de Clermont
Statistics
Citations: 48
Authors: 12
Affiliations: 6
Identifiers
Doi:
10.1186/1475-2875-8-88
e-ISSN:
14752875
Research Areas
Infectious Diseases
Noncommunicable Diseases