Sialyltransferase inhibitors : consideration of molecular shape and charge/hydrophobic interactions

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DOIResolve DOI: http://doi.org/10.1016/j.carres.2012.12.017
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TypeArticle
Journal titleCarbohydrate Research
ISSN0008-6215
Volume378
Pages4555; # of pages: 11
Subject1,2,3-Triazole; 2-Deoxy-2; Click chemistry; Sialic acids; Sialyltransferase; Sialyltransferease inhibitors>; 2-Deoxy-2,3-dehydro-acetylneuraminic acid; Amino acids; Bacteria; Binding energy; Carboxylic acids; Hydrophobicity; Molecules; Nitrogen compounds; Sulfur compounds; Synthesis (chemical); Enzyme inhibition; 1,2,3 triazole derivative; benzoic acid derivative; cytidine; cytidine phosphate n acetylneuraminic acid; phosphate; sialyltransferase; sulfanilamide; sulfonamide; article; binding affinity; Campylobacter jejuni; chemical structure; click chemistry; competitive inhibition; enzyme inhibition; glycosylation; hydrogen bond; hydrophobicity; molecular docking; molecular interaction; priority journal; Campylobacter jejuni
AbstractIn order to evaluate the importance of molecular shape of inhibitor molecules and the charge/H-bond and hydrophobic interactions, we synthesized three types of molecules and tested them against a sialyltransferase. The first type of compounds were designed as substrate mimics in which the phosphate in CMP-Neu5NAc was replaced by a non-hydrolysable, uncharged 1,2,3-triazole moiety. The second type of compound contained a 2-deoxy-2,3-dehydro-acetylneuraminic moiety which was linked to cytidine through its carboxylic acid and amide linkers. In the third type of compound the sialyl phosphate was substituted by an aryl sulfonamide which was then linked to cytidine. Inhibition study of these cytidine conjugates against Campylobacter jejuni sialyltransferase Cst 06 showed that the first type of molecules are competitive inhibitors, whereas the other two could only inhibit the enzyme non-competitively. The results indicate that although the binding specificity may be guided by molecular shape and H-bond interaction, the charge and hydrophobic interactions contributed most to the binding affinity.
Publication date
PublisherElsevier Ltd.
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Institute for Biological Sciences (IBS-ISB)
Peer reviewedYes
IdentifierS0008621512005095
NPARC number21269957
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Record identifierc6ebca10-a135-4907-acf2-aa07fc9fad31
Record created2013-12-13
Record modified2016-08-19
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