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Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2004 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 47, no 1, 110-22 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. Vol. 47, no 1, 110-22 p.
Keyword [en]
Amides/*chemical synthesis/chemistry/pharmacology, Animals, Aspartic Endopeptidases/*antagonists & inhibitors/chemistry, Cathepsin D/*antagonists & inhibitors, Cells; Cultured, Computer Simulation, Erythrocytes/parasitology, Ethylenes/*chemistry, Humans, Models; Molecular, Molecular Conformation, Plasmodium falciparum/drug effects/*enzymology, Protein Binding, Research Support; Non-U.S. Gov't, Stereoisomerism, Structure-Activity Relationship, Thermodynamics
National Category
Pharmaceutical Sciences Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-72743DOI: 10.1021/jm030933gPubMedID: 14695825OAI: oai:DiVA.org:uu-72743DiVA: diva2:100654
Available from: 2005-05-27 Created: 2005-05-27Bibliographically approved
In thesis
1. Design and Synthesis of Malarial Aspartic Protease Inhibitors
Open this publication in new window or tab >>Design and Synthesis of Malarial Aspartic Protease Inhibitors
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malaria is one of the major public health problems in the world. Approximately 500 million people are afflicted and almost 3 million people die from the disease each year. Of the four causative species Plasmodium falciparum is the most lethal. Due to the rapid spread of parasite resistance there is an urgent need for new antimalarial drugs with novel mechanisms of action. Several promising targets for drug intervention have been revealed.

This thesis addresses the parasitic aspartic proteases termed plasmepsins (Plm), which are considered crucial to the hemoglobin catabolism essential for parasite survival. The overall aim was to identify inhibitors of the P. falciparum Plm I, II, and IV. More specific objectives were to attain activity against P. falciparum in infected erythrocytes and selectivity versus the most homologous human aspartic protease cathepsin D (Cat D). To guide the design process the linear interaction energy (LIE) method was employed in combination with molecular dynamics.

Initial investigations of the stereochemical requirements for inhibition resulted in identification of an L-mannitol derived scaffold encompassing a 1,2-dihydroxyethylene transition state isostere with affinity for Plm II. Further modifications of this scaffold provided inhibitors of all three target plasmepsins (Plm I, II, and IV). Apart from the stereochemical analysis three major kinds of manipulation were explored: a) P1/P1′ and P2/P2′ side chain alterations, b) replacement of amide bonds by diacylhydrazine, 1,3,4-oxadiazole, and 1,2,4-triazole, and c) macrocyclization. Several inhibitors of Plm I and II with Ki values below 10 nM were discovered and one Plm IV selective inhibitor comprising two oxadiazole rings was found which represents the most potent non-peptide Plm IV inhibitor (Ki = 35 nM) reported to date. Some of the identified plasmepsin inhibitors demonstrated significant activity against P. falciparum in infected erythrocytes and all inhibitors showed a considerable selectivity for the plasmepsins over the human Cat D.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 93 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 5
Keyword
Pharmaceutical chemistry, malaria, plasmepsin, aspartic protease, protease inhibitor, macrocycle, Farmaceutisk kemi
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-4833 (URN)91-554-6177-8 (ISBN)
Public defence
2005-04-15, B41, Uppsala Biomedical Centre (BMC), Husarg. 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2005-03-23 Created: 2005-03-23 Last updated: 2009-08-17Bibliographically approved
2. Molecular Simulation of Enzyme Catalysis and Inhibition
Open this publication in new window or tab >>Molecular Simulation of Enzyme Catalysis and Inhibition
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The reaction mechanisms for the hemoglobin degrading enzymes in the Plasmodium falciparum malaria parasite, plasmepsin II (Plm II) and histo-aspartic protease (HAP), have been analyzed by molecular simulations. The reaction free energy profiles, calculated by the empirical valence bond (EVB) method in combination with molecular dynamics (MD) and free energy perturbation (FEP) simulations are in good agreement with experimental data. Additional computational methods, such as homology modelling and automated substrate docking, were necessary to generate a 3D model and a reactive substrate conformation before the reaction mechanism in HAP could be investigated. HAP is found to be an aspartic protease with a peptide cleaving mechanism similar to plasmepsin II. The major difference between these enzymes is that the negatively charged tetrahedral intermediate is stabilized by the charged histidine in HAP while in Plm II it is a neutral aspartic acid. Also the reaction mechanism for two other aspartic proteases, cathepsin D and HIV-1 protease, was simulated. These enzymes are relevant both for the inhibitor selectivity and for obtaining a general picture of catalysis in aspartic proteases.

Another project involves inhibitor design towards plasmepsins. In particular, Plm II directed inhibitors based on the dihydroxyethylene scaffold have been characterized computationally. Molecular dynamics (MD) simulations were used to propagate the investigated system through time and to generate ensembles used for the calculation of free energies. The ligand binding affinities were calculated with the linear interaction energy (LIE) method. The most potent inhibitor had a Ki value of 6 nM and showed 78 % parasite inhibition when tested on red blood cells infected by malaria parasite P. falciparum.

Citrate synthase is part of the citric acid cycle and is present in organisms that live in cold sea water as well as hot springs. The temperature adaptation of citrate synthase to cold and heat was investigated in terms of the difference in transition state stabilization between the psychrophilic, mesophilic and hyperthermophilic homologues. The EVB, FEP and MD methods were used to generate reaction free energy profiles. The investigated energetics points toward the electrostatic stabilization during the reaction as the major difference between the different citrate synthase homologues. The electrostatic stabilization of the transition state is most effective in the following order of the citrate synthase homologues: hyperthermophile, mesophile, psycrophile. This could be a general rule for temperature adaptation of enzyme catalysis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 56 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 270
Keyword
Theoretical chemistry, enzyme catalysis, enzyme inhibition, computer simulations, molecular dynamics, empirical valence bond method, structure-based inhibitor design, Teoretisk kemi
Identifiers
urn:nbn:se:uu:diva-7468 (URN)978-91-554-6794-6 (ISBN)
Public defence
2007-03-02, C8:305, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2007-02-07 Created: 2007-02-07 Last updated: 2010-04-28Bibliographically approved

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Ersmark, KarolinaBjelic, SinisaHallberg, Anders

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