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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Binding Sites
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Binding, Competitive
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Cathepsin D / antagonists & inhibitors
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Crystallography, X-Ray
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Cyclization
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Drug Design
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Humans
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Macrocyclic Compounds / chemical synthesis
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology*
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Models, Chemical
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Models, Molecular
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Molecular Conformation
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / enzymology*
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Protozoan Proteins
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Structure-Activity Relationship
Substances
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Macrocyclic Compounds
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Protease Inhibitors
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Protozoan Proteins
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Aspartic Acid Endopeptidases
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plasmapepsin IV
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plasmepsin
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plasmepsin II
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Cathepsin D