title: Identification of allosteric-activating drug leads for human liver pyruvate kinase.
abstract: There is a growing appreciation of the beneficial attributes of allosteric drugs. However, the development of this special class of drugs has in large part been via serendipitous findings from high-throughput screens of drug libraries. Limited success at deliberately identifying allosteric drugs may be due to a focus on enzyme inhibitors, a parallel to the historic focus on competitive inhibitors. In contrast to inhibition, activation of an enzyme by a small molecule can only occur through a limited number of mechanisms, mainly allosteric regulation. Activation of human liver pyruvate kinase (hL-PYK) in an effort to create a glycolytic/gluconeogenic futile cycle is one potential mechanism to counteract hyperglycemia. Using hL-PYK, we demonstrate the potential of drug library screens to identify allosteric-activator drug leads.
authors: Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, KS, USA. afenton@kumc.edu
authors: Aron W
authors: AW
authors: Fenton
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000201:enzymology*; D010728:Phosphoenolpyruvate / Q000494:pharmacology; D011770:Pyruvate Kinase / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D010728:Phosphoenolpyruvate; D011770:Pyruvate Kinase