Design of New Plasmepsin Inhibitors: A Virtual High Throughput Screening Approach on the EGEE Grid

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• 作者：Vinod Kasam ; Marc Zimmermann ; Astrid Maa ; Horst Schwichtenberg ; Antje Wolf ; Nicolas Jacq ; Vincent Breton ; Martin Hofmann-Apitius
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2007
• 出版时间：September 2007
• 年：2007
• 卷：47
• 期：5
• 页码：1818 - 1828
• 全文大小：718K
• 年卷期：v.47,no.5(September 2007)
• ISSN：1549-960X

文摘

Though different species of the genus Plasmodium may be responsible for malaria, the variant caused by P.falciparum is often very dangerous and even fatal if untreated. Hemoglobin degradation is one of the keymetabolic processes for the survival of the Plasmodium parasite in its host. Plasmepsins, a family of asparticproteases encoded by the Plasmodium genome, play a prominent role in host hemoglobin cleavage. In thispaper we demonstrate the use of virtual screening, in particular molecular docking, employed at a verylarge scale to identify novel inhibitors for plasmepsins II and IV. A large grid infrastructure, the EGEEgrid, was used to address the problem of large computation resources required for docking hundreds ofthousands of chemical compounds on different plasmepsin targets of P. falciparum. A large compoundlibrary of about 1 million chemical compounds was docked on 5 different targets of plasmepsins using twodifferent docking software, namely FlexX and AutoDock. Several strategies were employed to analyze theresults of this virtual screening approach including docking scores, ideal binding modes, and interactions tokey residues of the protein. Three different classes of structures with thiourea, diphenylurea, and guanidinoscaffolds were identified to be promising hits. While the identification of diphenylurea compounds is inaccordance with the literature and thus provides a sort of "positive control", the identification of novelcompounds with a guanidino scaffold proves that high throughput docking can be effectively used to identifynovel potential inhibitors of P. falciparum plasmepsins. Thus, with the work presented here, we do not onlydemonstrate the relevance of computational grids in drug discovery but also identify several promisingsmall molecules which have the potential to serve as candidate inhibitors for P. falciparum plasmepsins.With the use of the EGEE grid infrastructure for the virtual screening campaign against the malaria causingparasite P. falciparum we have demonstrated that resource sharing on an eScience infrastructure such asEGEE provides a new model for doing collaborative research to fight diseases of the poor.