Doctor of Philosophy
School of Chemistry
Nguyen, Phuong Thuy Viet, In silico drug discovery targeting Chikungunya virus, Doctor of Philosophy thesis, School of Chemistry, University of Wollongong, 2015. http://ro.uow.edu.au/theses/4452
In recent years, there has been an emergence or re-emergence of Chikungunya virus (CHIKV), a member of the alphavirus. The virus is one of the arboviruses, and it is classified as a neglected tropical disease in more than 55 different countries in the world, including many African and Asian countries, Europe, Americas, and Australia. In 2008, it was listed in the US National Institute of Allergy and Infectious Disease (NIAID) category C priority pathogen due to its morbidity and mortality rates. In addition to damaging global health, the virus also imposes a huge economic burden on affected countries. However, there is currently no licensed vaccine or effective drug to combat the disease. Up to now, there have been few studies focusing on finding potential inhibitors of CHIKV. Taking advantage of all available data about CHIKV and a combination of different computational methods, this study aimed to discover and develop an approach leading to identifying inhibitors against this virus. The study targeted the non-structural proteins, nsP3 macrodomain and nsP2 protease, which play crucial roles in the viral replication and transcription (Chapter 2 and Chapter 3), and the envelope glycoprotein complexes responsible for virus entry and attachment (Chapter 4). Initially, this study searched for potential binding pockets of the CHIKV protein structures. A combination of computational tools including molecule docking, virtual screening, molecule dynamics simulations, and binding free energy calculations were used in this approach. A number of lead compounds to fight CHIKV disease were identified. The insights into the interactions between CHIKV inhibitors and their targets were elucidated. Our findings open a way which would be helpful for the further research on antiviral rational drug design, especially design of inhibitors for CHIKV and also contribute to the guidelines for the drug discovery and development.