title: Computational inhibitor design against malaria plasmepsins.
abstract: Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I-IV in view of the interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations is analyzed.
authors.affiliation: Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Box 596, SE-75124 Uppsala, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Bjelic
authors.forename: M
authors.initials: M
authors.lastname: Nervall
authors.forename: H
authors.initials: H
authors.lastname: Gutiérrez-de-Terán
authors.forename: K
authors.initials: K
authors.lastname: Ersmark
authors.forename: A
authors.initials: A
authors.lastname: Hallberg
authors.forename: J
authors.initials: J
authors.lastname: Aqvist
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010961:Plasmodium / Q000187:drug effects / Q000201:enzymology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary
chemical_list: D000962:Antimalarials; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin