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Inhibitor binding to the Plasmepsin IV aspartic protease from Plasmodium falciparum
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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2006 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 45, no 35, 10529-10541 p.Article in journal (Refereed) Published
Abstract [en]

Plasmepsin IV (Plm IV) is one of the aspartic proteases present in the food vacuole of the malaria parasite Plasmodium falciparum involved in host hemoglobin degradation by the parasite. Using a series of previously synthesized plasmepsin inhibitors [Ersmark, K., et al. (2005) J. Med. Chem. 48, 6090-106], we report here experimental data and theoretical analysis of their inhibitory activity toward Plm IV. All compounds share a 1,2-dihydroxyethylene unit as the transition state mimic. They possess symmetric P1 and P1' side chains and either a diacylhydrazine, a five-membered oxadiazole ring, or a retroamide at the P2 and P2' positions. Experimental binding affinities are compared to those predicted by the linear interaction energy (LIE) method and an empirical scoring function, using both a crystal structure and a homology model for the enzyme. Molecular dynamics (MD) simulations of the modeled complexes allow a rational interpretation of the structural determinants for inhibitor binding. A ligand bearing a P2 and P2' symmetric oxadiazole which is devoid of amide bonds is identified both experimentally and theoretically as the most potent inhibitor of Plm IV. For the P2 and P2' asymmetric compounds, the results are consistent with earlier predictions regarding the mode of binding of this class of inhibitors to Plm II. Theoretical estimation of selectivity for some compounds is also reported. Significant features of the Plm IV binding pocket are discussed in comparison to related enzymes, and the results obtained here should be helpful for further optimization of inhibitors.

Place, publisher, year, edition, pages
2006. Vol. 45, no 35, 10529-10541 p.
National Category
Medical and Health Sciences Biological Sciences
URN: urn:nbn:se:uu:diva-96522DOI: 10.1021/bi0609669ISI: 000240079700013PubMedID: 16939205OAI: oai:DiVA.org:uu-96522DiVA: diva2:171124
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 372
Molecular biology, Plasmodium falciparum, plasmepsins, linear interaction energy, docking, HIV1 reverse trancriptase, Molekylärbiologi
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
Available from: 2007-11-23 Created: 2007-11-23Bibliographically approved

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Gutiérrez-de-Terán, HugoHallberg, Anders
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