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Atomistic Modelling and Experimental Validation of Enzyme-Inhibitor Interactions of Dengue Fever Virus Methyltransferase: Towards new approaches to target neglected tropical diseases.

Research Project
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01.10.2007
 - 31.12.2014

Dengue fever is a viral infectious disease that is prevalent in tropical regions. It is transmitted by mosquitoes and annually affects 50 to 100 million people worldwide. No vaccinations or specific drug treatments are available. Several of the virus' proteins are essential for its pathogenicity and are required by the virus to reproduce in host cells. In cases where three-dimensional structural models of the binding site of the proteins are known, computer simulations (i.e. virtual screening or molecular docking) can be used to simulate possible interaction between these proteins and small inhibitor molecules with the potential to become drug candidates. However, current algorithms used in virtual screening must make a number of approximations in order to be able to screen a large number of compounds within reasonable time. In contrast, atomistic simulations based on the physicochemical properties of molecules using Newton's laws of motion to determine the strength of binding between ligand and receptor molecules can provide more accurate, but computationally more demanding, predictions of the affinity with which a molecule binds to specific site in a protein. In this study, we focus our computational work on simulating the binding of small-molecule inhibitors to the viral enzyme NS5 methyltransferase. In a first step, a library of commercially available chemical compounds is searched by virtual screening for molecules likely to bind to the viral enzyme. Chemical compounds emerging from this study as possible inhibitors of dengue methyltransferase will be tested in biochemical and biological assays for their ability to inhibit viral replication in cultured cells. For this point, we are closely collaborating with the Novartis Institute for Tropical Diseases in Singapore. The results of the experimental measurements will in return increase our understanding of the physicochemical interactions governing methyltransferase inhibitor interactions and allow us to improve the accuracy of our molecular modeling simulations by calibrating interaction parameters with experimental binding affinities. Despite the clinical interest in MTase as drug target, little is known about the enzymatic mechanism of the methyl transfer reaction of this class of methyl transferases. In the second phase of the project, we have therefore focused on detailed molecular dynamics simulations of the transfer reaction. We moreover hope that this research will contribute to the discovery of new lead compounds against neglected tropical diseases, leading to the development of drugs that are offered at cost in the affected countries.

Collaborations & Cooperations

2014 - Participation or Organization of Collaborations on an international level
Canard, Bruno, Laboratoire AFMB CNRS, Universités Aix-Marseille, Research cooperation
2014 - Participation or Organization of Collaborations on an international level
Coutard, Bruno, Laboratoire AFMB CNRS, Universités Aix-Marseille, Research cooperation
2010 - Participation or Organization of Collaborations on an international level
Lim, Siew Pheng, NITD Novartis Institute for Tropical Diseases, Research cooperation
2010 - Participation or Organization of Collaborations on an international level
Sanschagrin, Paul, Schrodinger, Research cooperation
2010 - Participation or Organization of Collaborations on an international level
Shenkin, Peter S., Schrodinger, Research cooperation
2010 - Participation or Organization of Collaborations on an international level
Sonntag, Sebastian, NITD Novartis Institute for Tropical Diseases, Research cooperation

Publications

Schmidt, Tobias, Bergner, Andreas and Schwede, Torsten (2014) ‘Modelling three-dimensional protein structures for applications in drug design’, Drug discovery today, 19(7), pp. 890–7. Available at: https://doi.org/10.1016/j.drudis.2013.10.027.

URLs
URLs

Schmidt, Tobias B., Schwede, Torsten and Meuwly, Markus (2014) ‘Computational Analysis of Methyl Transfer Reactions in Dengue Virus Methyltransferase’, Journal of Physical Chemistry B, 118(22), pp. 5882–5890. Available at: https://doi.org/10.1021/jp5028564.

URLs
URLs

Podvinec, Michael et al. (2010) ‘Novel Inhibitors of Dengue Virus Methyltransferase : discovery by in vitro-driven virtual screening on a Desktop Computer Grid’, Journal of Medicinal Chemistry, 53(4), pp. 1483–95. Available at: https://doi.org/10.1021/jm900776m.

URLs
URLs

Members (4)

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Torsten Schwede

Principal Investigator
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Markus Meuwly

Co-Investigator
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Michael Podvinec

Project Member
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Tobias Schmidt

Project Member