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Computational inhibitor design against malaria plasmepsins
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.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2007 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 64, no 17, 2285-2305 p.Article in journal (Refereed) Published
Abstract [en]

Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I–IV in view of the interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations is analyzed.

Place, publisher, year, edition, pages
2007. Vol. 64, no 17, 2285-2305 p.
Keyword [en]
Malaria, plasmepsin, inhibitor design, reaction mechanism, molecular dynamics, linear interaction energy method
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96524DOI: 10.1007/s00018-007-7102-2ISI: 000249204800011OAI: oai:DiVA.org:uu-96524DiVA: diva2:171126
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2014-05-08Bibliographically approved
In thesis
1. Binding Free Energy Calculations on Ligand-Receptor Complexes Applied to Malarial Protease Inhibitors
Open this publication in new window or tab >>Binding Free Energy Calculations on Ligand-Receptor Complexes Applied to Malarial Protease Inhibitors
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malaria is a widespread disease caused by parasites of the genus Plasmodium. Each year 500 million clinical cases are reported resulting in over one million casualties. The most lethal species, P. falciparum, accounts for ~90% of the fatal cases and has developed resistance to chloroquine. The resistant strains are a major problem and calls for novel drugs.

In this thesis, the process of computational inhibitor design is illustrated through the development of P. falciparum aspartic protease inhibitors. These proteases, called plasmepsins, are part of the hemoglobin degradation chain. The hemoglobin is degraded during the intraerythrocytic cycle and serves as the major food source. By inhibiting plasmepsins the parasites can be killed by starvation.

Novel inhibitors with very high affinity were found by using a combination of computational and synthetic chemistry. These inhibitors were selective and did not display any activity on human cathepsin D. The linear interaction energy (LIE) method was utilized in combination with molecular dynamics (MD) simulations to estimate free energies of binding. The MD simulations were also used to characterize the enzyme–inhibitor interactions and explain the binding on a molecular level.

The influence of the partial charge model on binding free energy calculations with the LIE method was assessed. Two semiempirical and six ab initio quantum chemical charge derivation schemes were evaluated. It was found that the fast semiempirical charge models are equally useful in free energy calculations with the LIE method as the rigorous ab initio charge models.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 372
Keyword
Molecular biology, Plasmodium falciparum, plasmepsins, linear interaction energy, docking, HIV1 reverse trancriptase, Molekylärbiologi
Identifiers
urn:nbn:se:uu:diva-8338 (URN)978-91-554-7043-2 (ISBN)
Public defence
2007-12-14, C2:301, BMC, Husarg. 3, Uppsala, 13:00
Opponent
Supervisors
Available from: 2007-11-23 Created: 2007-11-23Bibliographically 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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Gutiérrez-de-Terán, Hugo

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