title: Design of new plasmepsin inhibitors: a virtual high throughput screening approach on the EGEE grid.
abstract: 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 key metabolic processes for the survival of the Plasmodium parasite in its host. Plasmepsins, a family of aspartic proteases encoded by the Plasmodium genome, play a prominent role in host hemoglobin cleavage. In this paper we demonstrate the use of virtual screening, in particular molecular docking, employed at a very large scale to identify novel inhibitors for plasmepsins II and IV. A large grid infrastructure, the EGEE grid, was used to address the problem of large computation resources required for docking hundreds of thousands of chemical compounds on different plasmepsin targets of P. falciparum. A large compound library of about 1 million chemical compounds was docked on 5 different targets of plasmepsins using two different docking software, namely FlexX and AutoDock. Several strategies were employed to analyze the results of this virtual screening approach including docking scores, ideal binding modes, and interactions to key residues of the protein. Three different classes of structures with thiourea, diphenylurea, and guanidino scaffolds were identified to be promising hits. While the identification of diphenylurea compounds is in accordance with the literature and thus provides a sort of "positive control", the identification of novel compounds with a guanidino scaffold proves that high throughput docking can be effectively used to identify novel potential inhibitors of P. falciparum plasmepsins. Thus, with the work presented here, we do not only demonstrate the relevance of computational grids in drug discovery but also identify several promising small 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 causing parasite P. falciparum we have demonstrated that resource sharing on an eScience infrastructure such as EGEE provides a new model for doing collaborative research to fight diseases of the poor.
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), 53754 Sankt Augustin, Germany. kasam@clermont.in2p3.fr
authors.forename: Vinod
authors.initials: V
authors.lastname: Kasam
authors.forename: Marc
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Astrid
authors.initials: A
authors.lastname: Maass
authors.forename: Horst
authors.initials: H
authors.lastname: Schwichtenberg
authors.forename: Antje
authors.initials: A
authors.lastname: Wolf
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jacq
authors.forename: Vincent
authors.initials: V
authors.lastname: Breton
authors.forename: Martin
authors.initials: M
authors.lastname: Hofmann-Apitius
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002224:Carbanilides / Q000737:chemistry / Q000494:pharmacology; D016000:Cluster Analysis; D003198:Computer Simulation; D003460:Crystallization; D019992:Databases as Topic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D006454:Hemoglobins / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008024:Ligands; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015203:Reproducibility of Results; D012984:Software; D013890:Thiourea / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D002224:Carbanilides; D006146:Guanidines; D006454:Hemoglobins; D007527:Isoenzymes; D008024:Ligands; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; D013890:Thiourea