Abstract 1820 PDK inhibitor virtual screening and experimental validation

The pyruvate dehydrogenase complex (PDC) is at the interface of glycolysis and the TCA cycle and is one of the major regulators of fuel selection and metabolic remodeling. Downregulation of PDC in cancer, type 2 diabetes, and heart disease has made this enzymatic complex a valuable drug target. In mammals, the PDC specific kinase inhibits PDC activity by phosphorylating the E1 subunit and blocking the pyruvate binding site. PDK inhibition is reversed by a pyruvate dehydrogenase specific phosphatase (PDP). Here we look to further activate PDC by inhibiting PDK with reversible synthetic inhibitors. The ZINC compound database currently contains over a billion compounds, where we have found about 10.5 million of these are characterized as drug-like, commercially available, and potentially in-stock. We prepared and docked this virtual library to known structures of PDK isozymes 1-4 to the lipoamide, ATP, and pzf3 binding sites. In the top 15K docked compounds of each PDK isozyme, we found only 8 compounds that were found to be in all four. These compounds have a common biphenyl structure that has not been identified in the literature. We synthesized six of these and tested them using a plate reader-based absorbance assay. We found two of these compounds to be active with IC50 values of approximately 30 μM. The project described was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Grant # 5P20GM103427 and R15GM15295-01.