Macrocyclic inhibitors of the malarial aspartic proteases plasmepsin I, II, and IV.
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.
Ersmark
Karolina
K
Department of Medicinal Chemistry, Uppsala University, BMC, PO Box 574, SE-751 23 Uppsala, Sweden.
Nervall
Martin
M
Gutiérrez-de-Terán
Hugo
H
Hamelink
Elizabeth
E
Janka
Linda K
LK
Clemente
Jose C
JC
Dunn
Ben M
BM
Gogoll
Adolf
A
Samuelsson
Bertil
B
Qvist
Johan
J
Hallberg
Anders
A
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
D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C451619:plasmapepsin IV; C089643:plasmepsin; C100637:plasmepsin II; D002402:Cathepsin D