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Predicting Binding Modes from Free Energy Calculations
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 Science and Technology, Biology, Department of Cell and Molecular Biology.
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2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 9, p. 2657-2667Article in journal (Refereed) Published
Abstract [en]

To produce reliable predictions of bioactive conformations is a major challenge in the field of structurebased inhibitor design and is a requirement for accurate binding free energy predictions with structurebased methods. A series of HIV-1 reverse transcriptase inhibitors was cross-docked using a non-native crystal structure that resulted in two distinct clusters of possible conformations. One of these clusters was compatible with an existing crystal structure, whereas the other displayed a flipped heterocyclic group. Binding free energies, using the non-native crystal structure, calculated from several scoring functions, were similar for the two clusters, and no conclusion about the binding mode could be drawn from these results. The two clusters could be separated through rescoring with the linear interaction method (LIE) in combination with molecular dynamics simulations, which leads to a binding mode prediction in line with experimental crystallographic data. Further, the LIE model produces the best correlation between experimental and calculated binding free energies among the tested scoring methods.

Place, publisher, year, edition, pages
2008. Vol. 51, no 9, p. 2657-2667
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96525DOI: 10.1021/jm701218jISI: 000255500000011PubMedID: 18410080OAI: oai:DiVA.org:uu-96525DiVA, id: diva2:171127
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2017-12-14Bibliographically 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. p. 54
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 372
Keywords
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

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