title: Macrocyclic inhibitors of the malarial aspartic proteases plasmepsin I, II, and IV.
abstract: The first macrocyclic inhibitor of the Plasmodium falciparum aspartic proteases plasmepsin I, II, and IV with considerable selectivity over the human aspartic protease cathepsin D has been identified. A series of macrocyclic compounds were designed and synthesized. Cyclizations were accomplished using ring-closing metathesis with the second generation Grubbs catalyst. These compounds contain either a 13-membered or a 16-membered macrocycle and incorporate a 1,2-dihydroxyethylene as transition state mimicking unit. The binding mode of this new class of compounds was predicted with automated docking and molecular dynamics simulations, with an estimation of the binding affinities through the linear interaction energy (LIE) method.
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, BMC, PO Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Ersmark
authors.forename: Martin
authors.initials: M
authors.lastname: Nervall
authors.forename: Hugo
authors.initials: H
authors.lastname: Gutiérrez-de-Terán
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: Adolf
authors.initials: A
authors.lastname: Gogoll
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Johan
authors.initials: J
authors.lastname: Qvist
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D001667:Binding, Competitive; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D018360:Crystallography, X-Ray; D003500:Cyclization; D015195:Drug Design; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015800:Protozoan Proteins; D013329:Structure-Activity Relationship
chemical_list: D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C451619:plasmapepsin IV; C089643:plasmepsin; C100637:plasmepsin II; D002402:Cathepsin D