Abstract
Inhibitors of human lactate dehydrogenase (hLDH5)—the enzyme responsible for the conversion of pyruvate to lactate coupled with oxidation of NADH to NAD+—are promising therapeutic agents against cancer because this enzyme is generally found to be overexpressed in most invasive cancer cells and is linked to their vitality especially under hypoxic conditions. Consequently, significant efforts have been made for the identification of small-molecule hLDH5 inhibitors displaying high inhibitory potencies. X-ray structure of hLDH5 complexes as well as molecular modeling studies contribute to identify and explain the main binding modes of hLDH5 inhibitors reported in literature. The purpose of this review is to analyze the main three-dimensional interactions between some of the most potent inhibitors and hLDH5, in order to provide useful suggestions for the design of new derivatives.
Highlights
Many malignant tumors are characterized by low oxygen conditions, which trigger the hypoxia-inducible factor 1α (HIF-1α)-mediated overexpression of a series of proteins that activate signaling pathways necessary for the survival of cancer cells under these conditions [1]
After the X-ray structure of hLDH5 in ternary complex with NADH and 1 was determined, various small molecule inhibitors have been co-crystallized with the enzyme and can be divided into different classes based on which portion of the active site they occupy within the binding complex
During the last eight years, great efforts from companies and academics have been made for identifying new hLDH5 inhibitors
Summary
Many malignant tumors are characterized by low oxygen conditions, which trigger the hypoxia-inducible factor 1α (HIF-1α)-mediated overexpression of a series of proteins that activate signaling pathways necessary for the survival of cancer cells under these conditions [1] Among these proteins, the human isoform 5 of lactate dehydrogenase (hLDH5)—a homotetramer composed of four. A subunits—plays an essential role in this process, since it catalyzes the NAD+ -coupled conversion of pyruvate—the end product of the glycolytic pathway—to lactate, which is excreted out of the cells This step allows the regeneration of the reduced cofactor NADH, permitting the continuation of glycolysis in cells that cannot rely on oxidative phosphorylation for energy production (“Warburg effect” or “aerobic glycolysis”). HLDH5 comprises both a substrate binding pocket, which usually hosts the small polar structure of the substrate pyruvate, and a cofactor binding site, where NADH, which is more extended than the substrate and is composed of lipophilic as well as polar portions, is located
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