Jump to main content
Jump to site search


Small molecule cores demonstrate non-competitive inhibition of lactate dehydrogenase

Abstract

Lactate dehydrogenase (LDH) has recently garnered attention as an attractive target for cancer therapies, owing to the enzyme’s critical role in cellular metabolism. Current inhibition strategies, employing substrate or cofactor analogues, are insufficiently specific for use as pharmaceutical agents. The possibility of allosteric inhibition of LDH was postulated on the basis of theoretical docking studies of a small molecule inhibitor to LDH. The present study examined structural analogues of this proposed inhibitor to gauge its potency and attempt to elucidate the molecular mechanism of action. These analogues display encouraging in vitro inhibition of porcine heart LDH, including micromolar Ki values and a maximum inhibition of up to 50% in the steady state. Furthermore, Michaelis-Menten kinetics and fluorescence data both suggest the simple, acetaminophen derivatives are non-competitive in binding to the enzyme. Kinetic comparisons of a panel of increasingly decorated structural analogues imply that the binding is specific, and the small molecule core provides a privileged scaffold for further pharmaceutical development of a novel, allosteric drug.

Back to tab navigation

Supplementary files

Publication details

The article was received on 21 Jun 2018, accepted on 11 Jul 2018 and first published on 13 Jul 2018


Article type: Research Article
DOI: 10.1039/C8MD00309B
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
  •   Request permissions

    Small molecule cores demonstrate non-competitive inhibition of lactate dehydrogenase

    B. Andrews and R. B. Dyer, Med. Chem. Commun., 2018, Accepted Manuscript , DOI: 10.1039/C8MD00309B

Search articles by author

Spotlight

Advertisements