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Abstract
Computational and experimental methodologies are often seen as competing resources. This is unfortunate because in the evaluation of complex biological phenomena often both methodologies are required to develop a complete understanding of the underlying science as well as an understanding of the system level behavior. Computational modeling approaches have become important in small molecule as well as macromolecular studies, especially when the problems are not readily accessible by experimental methods or when the computational methods can supplement the results obtained from experimental techniques and provide a basis for interpretation of the data. This dissertation reports computational studies of choline acetyltransferase inhibitors, the oxidized form of nuclear factor-kappa B homodimer and the complex structure of vascular endothelial growth factor (VEGF) and SPARC. A variety of ligand and structure-based molecular modeling techniques have been used throughout the dissertation research. Work investigating choline acetyltransferase inhibitors employed ligand-based methods like 3D-QSAR +to explore trans-1-methyl-4-(1-naphthylvinyl) pyridinium (MNVP) analogs and predict structural features that are essential for selective and potent inhibition. The information on the molecules sharing a given activity and their most similar analogs that do not exhibit this activity was used to develop models that can be used to discriminate between active and inactive compounds prior to their synthesis. The question of structure, function and nuclear entry of the oxidized form of NF-B homodimer was explored through protein modeling and molecular dynamics methods. It is our hypothesis that after I-B degradation the two subunits of the NF-B homodimer adopt a closed conformation through a hinge movement involving the flexible linker region, making the dimer structure compact to facilitate its nuclear translocation. The results from molecular modeling studies help to determine how the disulfide bridge formation between the two subunits of the dimer facilitates nuclear entry, through comparison with the experimentally known structure of the reduced form. The structure of the complex between vascular endothelial growth factor (VEGF) with anti-angiogenic molecule, SPARC (secreted protein acidic and rich in cysteine) is predicted through protein-protein docking simulation used in conjunction with biological data. Docking method was used to model the complex structure, in an effort to identify the specific interactions between the two molecules, which can be used as a basis for guiding future studies aimed at identifying inhibitors for VEGF-induced angiogenesis