Docking Studies and Synthesis of a Gracilin A Derivative with Increased Predicted Affinity to Cyclophilin D
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Access changed 9/21/23.
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Alzheimer’s Disease (AD) is responsible for the progressive brain degradation of 3 million U.S. citizens annually and is the sixth leading cause of death in America. This disease has no current cure. The goal of this project is to synthesize a novel neuroprotective derivative of gracilin A. Gracilin A is a unique metabolite derived from the marine sponge Spongionella gracilis and member of the spongiane diterpenoid family. The new molecule will act as a potent inhibitor of pathways responsible for oxidative damage to neurons directly precursing the onset of AD.
Recently, derivatives of gracilin A were synthesized, analyzed, and determined to be potent neuroprotectors and immunosuppressants. These derivatives exhibit such effects by binding to cyclophilin D (CypD) thereby blocking opening of the mitochondrial permeability transition pore (mPTP). Docking experiments were performed to predict derivatives of gracilin A which would exhibit selectivity in binding to a CypD which blocks the mPTP and enhances neuroprotection over binding to Cyclophilin A (CypA). The compound proposed for total synthesis is based on a pre-existing mono-acetoxy furanose derivative of gracilin, compound 29a. The new molecule is characterized by the presence of a diol and absence of a gem dimethyl group.