BPS2026 – Targeting the lipoamide binding site of pyruvate dehydrogenase kinase through structure-based virtual screening with experimental validation

The pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that connect glycolysis to the TCA cycle. The PDC is negatively regulated by its own specific kinase, the pyruvate dehydrogenase kinase (PDK). Overexpression of PDK, and therefore decreased activity of PDC, is associated with numerous metabolic disorders including various forms of cancer, type 2 diabetes, and heart disease. One strategy used to try and counter the overt inhibition of PDC by PDK is to inhibit PDK through known target sites such as the lipoamide binding site. To this end, we virtually screened 9 million compounds from the Enamine database targeting the lipoamide binding site of PDK1-2 isozymes using different computational strategies. Over 100 compounds were tested using an in vitro enzymatic assay where compounds yielding low micromolar IC50s are discussed including computational strategies used.