Small molecule cores demonstrate non-competitive inhibition of lactate dehydrogenase

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 a...

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Bibliographic Details
Published in:MedChemComm 2018-08, Vol.9 (8), p.1369-1376
Main Authors: Andrews, Brooke A, Dyer, R Brian
Format: Article
Language:English
Subjects:
Acetaminophen
Allosteric properties
Binding
Cancer
Dehydrogenase
Dehydrogenases
Docking
Enzymes
Fluorescence
Inhibitors
Kinases
Kinetics
L-Lactate dehydrogenase
Lactate dehydrogenase
Lactic acid
Metabolism
Pharmaceuticals
Substrate inhibition
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Summary: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 inhibition of porcine heart LDH, including micromolar 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.
ISSN:2040-2503
2040-2511
DOI:10.1039/c8md00309b