title: Computational analysis of plasmepsin IV bound to an allophenylnorstatine inhibitor.
abstract: The plasmepsin proteases from the malaria parasite Plasmodium falciparum are attracting attention as putative drug targets. A recently published crystal structure of Plasmodium malariae plasmepsin IV bound to an allophenylnorstatine inhibitor [Clemente, J.C. et al. (2006) Acta Crystallogr. D 62, 246-252] provides the first structural insights regarding interactions of this family of inhibitors with plasmepsins. The compounds in this class are potent inhibitors of HIV-1 protease, but also show nM binding affinities towards plasmepsin IV. Here, we utilize automated docking, molecular dynamics and binding free energy calculations with the linear interaction energy LIE method to investigate the binding of allophenylnorstatine inhibitors to plasmepsin IV from two different species. The calculations yield excellent agreement with experimental binding data and provide new information regarding protonation states of active site residues as well as conformational properties of the inhibitor complexes.
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, BMC, P.O. Box 596, 751 24 Uppsala, Sweden.
authors.forename: Hugo
authors.initials: H
authors.lastname: Gutiérrez-de-Terán
authors.forename: Martin
authors.initials: M
authors.lastname: Nervall
authors.forename: Ben M
authors.initials: BM
authors.lastname: Dunn
authors.forename: Jose C
authors.initials: JC
authors.lastname: Clemente
authors.forename: Johan
authors.initials: J
authors.lastname: Aqvist
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020134:Catalytic Domain; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008958:Models, Molecular; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000201:enzymology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D010654:Phenylbutyrates; D011480:Protease Inhibitors; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin