A Molecular Modeling Approach Towards The Discovery Of Inhibitors For Rift Valley Fever Virus Nucleocapsid Protein

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Computer Science and Bioinformatics Program


Master of Science

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Rift Valley Fever Virus (RVFV) is a zoonotic pathogen belonging to the genusPhlebovirus and family Bunyaviridae within the negative-strand RNA genome viruses superfamily. It causes severe illnesses in animals and humans yet there are no FDA approved drugs or human vaccines. RVFV is spread by mosquitoes or contact with infected animal carcasses and is endemic to Africa and Peninsula regions of the Middle East, but there is concern that it could spread to other regions of the world given that the mosquito vectors are more widely distributed than the pathogen itself. It is cross-listed by the US Department of Agriculture (USDA) and Department of Human and Health Services (DHHS) as a select agent, which are organisms or toxins with the potential of being used for bioterrorism and for which there are no available countermeasures. With crystal structures of RVFV nucleocapsid (N) protein becoming recently available, it was hypothesized that identification of its mode of interaction with RNA could lead to selection of compounds with the ability to inhibit genome packaging. The main goal of this thesis research was to study through computational techniques the interaction of N with the RNA genome with an aim of identifying putative inhibitors by screening drug-like molecular libraries. The coordinates for the crystal structures of N were obtained from Protein Data Bank (PDB) and used in dockings and virtual screening. Using sequence alignment and molecular modeling, invariant residues in phleboviral N proteins were mapped to the model with a view of refining the modes of interactions. The RVFV N protein was analyzed for potential drug/ligand binding cavities with Pocket-Finder while molecules derived from the NCI Diversity Set III, Drug Bank and PubChem libraries were screened with AutoDock Vina using the PyRx virtual screening tool. Docking Server and Discovery studio were used to determine protein-ligand interactions. These studies successively developed a theoretical model describing the N-protein interactions with RNA. Further, we identified six compounds as potential inhibitors which subject to experimental verification, could serve as a starting point for the development of drugs that target the genome packaging step in RVFV and related RNA viruses.