Diclofenac Identified as a Kynurenine 3-Monooxygenase Binder and Inhibitor by Molecular Similarity Techniques

ACS Omega
Steven ShaveManfred Auer

Abstract

In this study, we apply a battery of molecular similarity techniques to known inhibitors of kynurenine 3-monooxygenase (KMO), querying each against a repository of approved, experimental, nutraceutical, and illicit drugs. Four compounds are assayed against KMO. Subsequently, diclofenac (also known by the trade names Voltaren, Voltarol, Aclonac, and Cataflam) has been confirmed as a human KMO protein binder and inhibitor in cell lysate with low micromolar KD and IC50, respectively, and low millimolar cellular IC50. Hit to drug hopping, as exemplified here for one of the most successful anti-inflammatory medicines ever invented, holds great promise for expansion into new disease areas and highlights the not-yet-fully-exploited potential of drug repurposing.

References

Feb 8, 1967·Biochemical and Biophysical Research Communications·H OkamotoO Hayaishi
May 18, 1999·Archives of Disease in Childhood. Fetal and Neonatal Edition·S ConroyI Choonara
Feb 15, 2000·European Journal of Biochemistry·J BretonA Isacchi
Mar 7, 2001·Applied and Environmental Microbiology·T A Slieman, W L Nicholson
Feb 1, 2002·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Imti Choonara, Sharon Conroy
Mar 26, 2003·Journal of Chemical Information and Computer Sciences·Christoph SteinbeckEgon Willighagen
Jul 10, 2003·Immunology and Cell Biology·John R Moffett, Ma Aryan Namboodiri
Mar 8, 2007·Journal of Computational Chemistry·Pedro J Ballester, W Graham Richards
Dec 1, 2007·Nucleic Acids Research·David S WishartMurtaza Hassanali
Sep 29, 2011·Nucleic Acids Research·Anna GaultonJohn P Overington
Oct 11, 2011·Journal of Cheminformatics·Noel M O'BoyleGeoffrey R Hutchison
Nov 16, 2012·Acta Crystallographica. Section D, Biological Crystallography·Chelsy Prince, Zongchao Jia
Apr 12, 2013·Nature·Marta AmaralNigel S Scrutton
Jan 2, 2014·Journal of Biomolecular Screening·Denise M LoweJonathan P Hutchinson
Oct 10, 2014·Journal of Biomolecular Screening·Kris WilsonScott P Webster
Jun 20, 2015·Nature Reviews. Drug Discovery·Michael J WaringAlex Weir
Mar 2, 2016·Journal of Health Economics·Joseph A DiMasiRonald W Hansen
Sep 28, 2016·Scientific Reports·Christos SkourasDamian J Mole
Mar 25, 2017·Bioorganic & Medicinal Chemistry Letters·John LiddleScott P Webster
Apr 4, 2017·British Journal of Pharmacology·Y ChaD Laifenfeld

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Citations

Aug 10, 2018·Frontiers in Chemistry·Ashutosh Kumar, Kam Y J Zhang
Feb 26, 2019·Frontiers in Molecular Biosciences·Robert S PhillipsJ Phillip Bowen
Nov 16, 2019·Future Medicinal Chemistry·Leonardo Rander Asse JuniorVinicius Gonçalves Maltarollo
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lizaveta GotinaAe Nim Pae
Dec 2, 2020·Trends in Pharmacological Sciences·Morgane ModouxHarry Sokol
Aug 18, 2020·Journal of Molecular Graphics & Modelling·Yılmaz Özkılıç, Nurcan Ş Tüzün

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Methods Mentioned

BETA
equilibrium dialysis

Software Mentioned

GraFit
ChEMBL
OpenEye
Autodock Vina
OpenBabel
Omega2

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