Molecular Dynamics of the Dengue Virus NS3/NS2b Protease

Abstract

Dengue is a vector tropical disease affecting millions of people, and may lead to death. Brazil is the country with the highest number of dengue and dengue hemorrhagic fever (D/DHF) cases combined.[1] In the sixth more populated country in the world, Pakistan, dengue has infected over 12,000 people and killed over 125 in 2011 alone.[2]Unfortunately, there are no specific medicines for the treatment of D/DHF and, once infected, the WHO recommendations are limited to observation and symptomatic treatment. Recent efforts have revealed a series of proteins essential to the dengue virus's life cycle, which may be used as targets for new medicines.[3]The aim of the present work is to understand the mechanism of action of such an enzyme, nonstructural protein NS3 protease complexed with the cofactor NS2b (NS3/NS2b), responsible for cleaving the viral polyprotein during the virus replication step, and the identification of molecules capable of effectively inhibiting this enzyme, thus preventing the virus from replicating.We will show molecular dynamics simulations of the NS3/NS2b complex, alone and in the presence of the substrate (Boc-Gly-Arg-Arg-AMC) in the active site, as well as hybrid QM/MM simulations for understanding the enzymatic mechanism.[1] World Health Organization. Drug for Neglected Diseases Initiative, 2009. Available from: http://www.dndi.org/. [visited 06/23/2009];[2] CNN International, Dengue fever kills 125, infects more than 12,000 in Pakistan - cnn.com, 2011, available from http://edition.cnn.com/2011/09/30/world/asia/pakistan-dengue-fever[Visited 10/01/2011][3] P. Erbel, N. Schiering, A. D’Arcy, M. Renatus, M. Kroemer, S.P. Lim, Z. Yin, T. H. Keller, S. G. Vasudevan, and U. Hommel, Nat. Struct. Mol. Biol. 13, 372-373.Support: CAPES, FACEPE