title: Synthesis of malarial plasmepsin inhibitors and prediction of binding modes by molecular dynamics simulations.
abstract: A series of inhibitors of the malarial aspartic proteases Plm I and II have been synthesized with L-mannitol as precursor. These inhibitors are characterized by either a diacylhydrazine or a five-membered oxadiazole ring replacing backbone amide functionalities. Molecular dynamics simulations were applied in the design process. The computationally predicted Plm II Ki values were generally in excellent agreement with the biological results. The diacylhydrazine was found to be superior over the oxadiazole as an amide bond replacement in the Plm I and II inhibitors studied. An extensive flexibility of the S2' pocket was captured by the simulations predicting the binding mode of the unsymmetrical inhibitors. Plm I and II inhibitors with single digit nanomolar Ki values devoid of inhibitory activity toward human Cat D were identified. One compound, lacking amide bonds, was found to be Plm IV selective and very potent, with a Ki value of 35 nM.
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, 751 23 Uppsala, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Ersmark
authors.forename: Martin
authors.initials: M
authors.lastname: Nervall
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamelink
authors.forename: Linda K
authors.initials: LK
authors.lastname: Janka
authors.forename: Jose C
authors.initials: JC
authors.lastname: Clemente
authors.forename: Ben M
authors.initials: BM
authors.lastname: Dunn
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Johan
authors.initials: J
authors.lastname: Aqvist
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry; D008353:Mannitol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D010963:Plasmodium falciparum / Q000201:enzymology; D011485:Protein Binding; D015800:Protozoan Proteins; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D000962:Antimalarials; D006834:Hydrazines; D010069:Oxadiazoles; D015800:Protozoan Proteins; D008353:Mannitol; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II; D002402:Cathepsin D