Molecular Dynamics of the Dengue Virus NS3/NS2B Protease in Presence of Inhibitor or Substrate

Abstract

Dengue is a neglected 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] However, recent news show that dengue virus reaches areas that had not been hit earlier as the Madeira Island (Portugal) [2], Florida (United States) [3], and in New Caledonia (Oceania) [4].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. [5].The objective of this study is to understand the mechanism of action of the nonstructural protein NS3 protease complexed with the cofactor NS2b (NS3/NS2b), responsible for cleaving the viral polyprotein during the virus replication step, and understanding of interaction of this protein with its substrate and inhibitor through molecular dynamics study.We will be present molecular dynamics simulations of the NS3/NS2b complex alone, in the presence of the substrate (Ala-Gly-Arg-Lys-Ser-Ile) or an inhibitor (Bzo-Nle-Lys-Arg-Arg-H) 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. http://www.dndi.org/. [06/23/2009];2. http://www.who.int/ith/updates/20121012/en/ [12/10/2012]3. http://edition.cnn.com/2013/08/27/health/florida-dengue/index.html [27/08/2013]4. http://newcaledoniatoday.wordpress.com/2013/04/06/150-contract-dengue-fever-a-day-in-new-caledonia/ [06/04/2013]5. Paul Erbel, Nikolaus Schiering, Allan D'Arcy, Martin Renatus, Markus Kroemer, Siew Pheng Lim, Zheng Yin, Thomas H. Keller, Subhash G. Vasudevan, and Ulrich Hommel, Nat. Struct. Mol. Biol. 13, 372-373.Support: CAPES, FACEPE.