Structure-Based Design, Molecular Docking Studies, Virtual Screening, and Synthesis of a Novel Sulfonamide Derivative of Gracilin A

Mitochondrial permeability transition is the final common pathway before apoptosis and has been tightly linked to neurodegeneration. As the only confirmed regulator of the mitochondrial permeability transition pore, cyclophilin D provides an attractive target for potential neuroprotective drugs. Current cyclophilin D inhibitors are non-selective and bind to other cyclophilin proteins, making them potent immunosuppressors. The natural product gracilin A has been shown to be effective in binding cyclophilins D and A, so this research aims to maximize the neuroprotective quality of gracilin A by increasing cyclophilin D binding affinity and selectivity. In these studies, a series of gracilin A derivatives were modeled based on a previously published derivative, compound 27b. This thesis will examine current literature concerning mitochondrial permeability transition as well as the design and synthesis of a promising potential drug lead, a sulfonamide derivative of compound 27b with increased binding affinity and selectivity for cyclophilin D.