Computer-aided drug design and synthesis of novel antivirals

• Main Author: Khedr, Mohammed Abdou
• Published: Cardiff University 2010
• Subjects: 615.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.584878

The Flaviviridae is a family of 66 viruses of which almost half have been associated with human disease. The most well-known members are: Hepatitis C virus (HCV), Dengue virus (DV), and West Nile virus (WNV). Diseases caused by these viruses are a global health problem that put an estimated 2.5 billion people at risk. At present, there are neither vaccines nor other treatments available to prevent or cure these diseases. Potential targets for the development of therapeutics against the virus are the viral protease and polymerase. The aims of this project are to design and synthesize compounds that can be used as inhibitors for these two key enzymes for Dengue. Structure-based drug design methods utilize knowledge of a three dimensional structure of an enzyme/receptor to develop small molecules able to bind to the desired target, generating a specific biological response. These computer-based methodologies are now becoming an integral part of the drug discovery process and, although the principles of molecular recognition are far from being completely understood, some marketed compounds (i.e. Zanamivir, Lopinavir) have been developed with the help the of successful application of structure-based design techniques. Different structure-based drug design approaches have been used to identify putative new inhibitors for the Dengue protease and polymerase. A pharmacophore query has been built based on the active site of the Dengue protease enzyme and then used for screening different databases for identification of potential inhibitors. For the polymerase, a fragment-based approach has been used to find the fragments that would interact more efficiently with a specific binding pocket on the enzyme. The virtual library obtained by linking the best scored fragment was then docked to identify the most promising structures to be synthesized. The identification of potent small molecules that bind to receptors and enzymes is one of the major goals of chemical and biological research.