title: Rational design and synthesis of substrate-product analogue inhibitors of α-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis.
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.
authors.affiliation: Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada. sbearne@dal.ca.
authors.forename: Mohan
authors.initials: M
authors.lastname: Pal
authors.affiliation: Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada. sbearne@dal.ca.
authors.forename: Mandar
authors.initials: M
authors.lastname: Khanal
authors.affiliation: Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada. sbearne@dal.ca.
authors.forename: Ryan
authors.initials: R
authors.lastname: Marko
authors.affiliation: Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada. sbearne@dal.ca.
authors.forename: Srinath
authors.initials: S
authors.lastname: Thirumalairajan
authors.affiliation: 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.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Bearne
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase