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.