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Computational Modelling of Inhibitor Binding to Human Thrombin
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
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2001 (English)In: Eur. J. Pharm. Sci., Vol. 12, no 4, 441-446 p.Article in journal (Refereed) Published
Abstract [en]

Thrombin is an essential protein involved in blood clot formation and an important clinical target, since disturbances of the coagulation process cause serious cardiovascular diseases such as thrombosis. Here we evaluate the performance of a molecular dynamics based method for predicting the binding affinities of different types ofhuman thrombin inhibitors. Far a series of eight ligands the method ranks their relative affinities reasonably well. The binding free energy difference between high and low affinity representatives in the test set is quantitatively reproduced, as well as the stereospecificity for a chiral inhibitor. The original parametrisation of this linear interaction energy method requires the addition of a constant energy term in the case of thrombin. This yields a mean unsigned error of 0.68 kcal/mol for the absolute binding free energies. This type of approach is also useful for elucidating three-dimensional structure-activity relationships in terms ofmicroscopic interactions of the ligands with the solvated enzyme. 

Place, publisher, year, edition, pages
2001. Vol. 12, no 4, 441-446 p.
National Category
Natural Sciences
URN: urn:nbn:se:uu:diva-45328DOI: 10.1016/S0928-0987(00)00185-8ISI: 000167531700011OAI: oai:DiVA.org:uu-45328DiVA: diva2:73235
Available from: 2006-03-15 Created: 2006-03-15 Last updated: 2013-02-18Bibliographically approved

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Ljungberg, Kajsa BÅqvist, J
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