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.

Cite this paper

@article{Ersmark2006MacrocyclicIO, title={Macrocyclic inhibitors of the malarial aspartic proteases plasmepsin I, II, and IV.}, author={Karolina Ersmark and Martin Nervall and Hugo Guti{\'e}rrez-de-Ter{\'a}n and Elizabeth Hamelink and Linda K Janka and Jos{\'e} C Clemente and Ben Dunn and Adolf Gogoll and Bertil B. Samuelsson and Johan Qvist and Anders Hallberg}, journal={Bioorganic & medicinal chemistry}, year={2006}, volume={14 7}, pages={2197-208} }