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Novel Cruzain Inhibitors for the Treatment of Chagas' Disease
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
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2012 (English)In: Chemical Biology and Drug Design, ISSN 1747-0277, Vol. 80, no 3, 398-405 p.Article in journal (Refereed) Published
Abstract [en]

The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T.similar to cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas disease.

Place, publisher, year, edition, pages
2012. Vol. 80, no 3, 398-405 p.
Keyword [en]
Chagas' disease, computer-aided drug discovery, cruzain, cruzipain, cysteine protease inhibitor, Trypanosoma cruzi
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-179897DOI: 10.1111/j.1747-0285.2012.01416.xISI: 000306664800007OAI: oai:DiVA.org:uu-179897DiVA: diva2:547535
Available from: 2012-08-28 Created: 2012-08-27 Last updated: 2015-01-23Bibliographically approved
In thesis
1. Advances in Ligand Binding Predictions using Molecular Dynamics Simulations
Open this publication in new window or tab >>Advances in Ligand Binding Predictions using Molecular Dynamics Simulations
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Biochemical processes all involve associations and dissociations of chemical entities. Understanding these is of substantial importance for many modern pharmaceutical applications. In this thesis, longstanding problems with regard to ligand binding are treated with computational methods, applied to proteins of key pharmaceutical importance. Homology modeling, docking, molecular dynamics simulations and free-energy calculations are used here for quantitative characterization of ligand binding to proteins. By combining computational tools, valuable contributions have been made for pharmaceutically relevant areas: a neglected tropical disease, an ion channel anti-drug-target, and GPCR drug-targets.

We report three compounds inhibiting cruzain, the main cysteine protease of the protozoa causing Chagas’ disease. The compounds were found through an extensive virtual screening study and validated with experimental enzymatic assays. The compounds inhibit the enzyme in the μM-range and are therefore valuable in further lead optimization studies.

A high-resolution crystal structure of the BRICHOS domain is reported, together with molecular dynamics simulations and hydrogen-deuterium exchange mass spectrometry studies. This work revealed a plausible mechanism for how the chaperone activity of the domain may operate.

Rationalization of structure-activity relationships for a set of analogous blockers of the hERG potassium channel is given. A homology model of the ion channel was used for docking compounds and molecular dynamics simulations together with the linear interaction energy method employed for calculating the binding free-energies.

The three-dimensional coordinates of two GPCRs, 5HT1B and 5HT2B, were derived from homology modeling and evaluated in the GPCR Dock 2013 assessment. Our models were in good correlation with the experimental structures and all of them placed among the top quarter of all models assessed. 

Finally, a computational method, based on molecular dynamics free-energy calculations, for performing alanine scanning was validated with the A2A adenosine receptor bound to either agonist or antagonist. The calculated binding free-energies were found to be in good agreement with experimental data and the method was subsequently extended to non-alanine mutations. With extensive experimental mutation data, this scheme is a valuable tool for quantitative understanding of ligand binding and can ultimately be used for structure-based drug design.

Place, publisher, year, edition, pages
Uppsala: Uppsala universitet, 2014. 51 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1172
free-energy perturbation, molecular dynamics, ligand binding, free-energy perturbation, linear interaction energy, binding free-energy, homology modeling, virtual screening, alanine scanning, amino acid mutagenesis, hERG, GPCR, adenosine receptor, serotonin receptor, BRICHOS, cruzain
National Category
Theoretical Chemistry Biological Sciences
urn:nbn:se:uu:diva-230777 (URN)978-91-554-9020-1 (ISBN)
Public defence
2014-10-15, B41, BMC, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2014-09-23 Created: 2014-08-29 Last updated: 2015-01-23

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