Rational design and synthesis of substrate-product analogue inhibitors of α-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis

Mohan Pal; Mandar Khanal; Ryan Marko; Srinath Thirumalairajan; Stephen L Bearne

doi:10.1039/c5cc08096g

Rational design and synthesis of substrate-product analogue inhibitors of α-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis

Chem Commun (Camb). 2016 Feb 14;52(13):2740-3. doi: 10.1039/c5cc08096g.

Authors

Mohan Pal¹, Mandar Khanal¹, Ryan Marko¹, Srinath Thirumalairajan¹, Stephen L Bearne²

Affiliations

¹ Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada. sbearne@dal.ca.
² Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada. sbearne@dal.ca and Department of Chemistry, Dalhousie University, Halifax, NS B3H 4R2, Canada.

PMID: 26759836
DOI: 10.1039/c5cc08096g

Abstract

2,2-Bis(4-isobutylphenyl)propanoyl-CoA and 2,2-bis(4-t-butylphenyl)propanoyl-CoA are rationally designed, gem-disubstituted substrate-product analogues that competitively inhibit α-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis with Ki values of 16.9 ± 0.6 and 21 ± 4 μM, respectively, exceeding the enzyme's affinity for the substrate by approximately 5-fold.

MeSH terms

Drug Design
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Ligands
Mycobacterium tuberculosis / enzymology*
Racemases and Epimerases / antagonists & inhibitors*
Racemases and Epimerases / metabolism
Substrate Specificity

Substances

Enzyme Inhibitors
Ligands
Racemases and Epimerases
alpha-methylacyl-CoA racemase