Small molecule cores demonstrate non-competitive inhibition of lactate dehydrogenase

MedChemComm
Brooke A Andrews, R Brian Dyer

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.

References

Jun 6, 1998·Advances in Protein Chemistry·G K Ackers
May 1, 1965·Journal of Molecular Biology·J MONODJ P CHANGEUX
May 8, 2007·Biophysical Journal·Linlin QiuRobert Callender
May 8, 2007·Biophysical Journal·J R Exequiel T PinedaSteven D Schwartz
May 20, 2008·Biophysical Journal·Nickolay ZhadinRobert Callender
Dec 24, 2008·Nature Reviews. Cancer·Jianming ZhangNathanael S Gray
May 23, 2009·Science·Matthew G Vander HeidenCraig B Thompson
Mar 29, 2011·Journal of Enzyme Inhibition and Medicinal Chemistry·Lorena Rodríguez-PáezCarlos Wong
Sep 6, 2011·Biochemistry·Leonor MichaelisRoger S Goody
Feb 23, 2012·Nature Chemistry·Sam Hay, Nigel S Scrutton
Aug 26, 2014·The Journal of Physical Chemistry. B·Michael J ReddishR Brian Dyer
Feb 11, 2015·Acta Crystallographica. Section D, Biological Crystallography·Subramaniapillai KolappanLisa Craig
Aug 19, 2015·Seminars in Cell & Developmental Biology·William J Israelsen, Matthew G Vander Heiden
Oct 21, 2015·Trends in Biochemical Sciences·Alexandr P Kornev, Susan S Taylor
Apr 23, 2016·Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy·Na-Na LuJing Gao
May 31, 2016·Cell·Alan MerkSriram Subramaniam
Jun 22, 2016·The Journal of Physical Chemistry Letters·Michael W Dzierlenga, Steven D Schwartz
Dec 14, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Robert Roskoski
May 13, 2017·Biophysical Journal·Michael J ReddishR Brian Dyer

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Citations

Apr 2, 2021·The Journal of Pharmacy and Pharmacology·Tim WenzelHenning Gieseler

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Methods Mentioned

BETA
size exclusion chromatography
Dynamic light scattering

Software Mentioned

Igor Pro
SEDFIT

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