Rational search for inhibitors of Dengue and Foot-and-Mouth Disease proteases

Abstract

Discovery of bioactive compounds, initially, was done by trial and error, usually, through randomly tests of different natural products against various diseases. Nowadays, the design of bioactive compounds is based on the structure knowledge of the ligand (Ligand Based Drug Design - LBDD) and/or of the biological target (structure based drug design - SBDD, that includes Virtual Screening (VS) procedure). In the virtual screening, selection of potential ligands are done computationally (in silico) using virtual libraries with huge number of compounds.Dengue Fever and Foot-and-Mouth Disease (FMD) are viral infections, that occur in Brazil and abroad, causing significant socio-economic impact. At the same time, it has to be point out that antivirals design search is necessary when the vaccine is not available (e.g. for Dengue virus) or for an outbreak control (e.g. for FMD virus, pathogen infecting, exclusively, animals). In this PhD project we propose to apply some SBDD methodological approaches, specially Virtual Screening (VS) protocols to commercial molecules library in order to generate models to select potential inhibitors of viral proteases of Dengue Fever and of FMD. All procedures have been previously implemented in the group. These studies will be done from the 3D structures of Dengue and FMD proteases, respectively, NS2B/NS3 and Lbpro taken from PDB or obtained by homology model. In addition, enzymatic inhibition assays will be done in order to perform validation and optimization of the generated in silico models. All inhibition assays will be carried out by myself in collaboration with Prof. Dr. L. Juliano group from Department of Biophysics, UNIFESP-SP. The proteases used in this project will be provided from his group. Finally, from the Virtual Screening (VS) generated models we intend to be able to contribute to the understanding of ligand-receptor interactions, respectively in the Dengue NS2B/NS3 and FMD Lbpro systems. (AU)