title: Sialyltransferase inhibitors: consideration of molecular shape and charge/hydrophobic interactions.
abstract: In 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.
authors: Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada K1A 0R6.
authors: Rishi
authors: R
authors: Kumar
authors: Ravindranath
authors: R
authors: Nasi
authors: Milan
authors: M
authors: Bhasin
authors: Nam
authors: N
authors: Huan Khieu
authors: Margaret
authors: M
authors: Hsieh
authors: Michel
authors: M
authors: Gilbert
authors: Harold
authors: H
authors: Jarrell
authors: Wei
authors: W
authors: Zou
authors: Harold J
authors: HJ
authors: Jennings
mesh_terms: D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016123:Campylobacter jejuni / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D012799:Sialyltransferases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D012799:Sialyltransferases
keywords: 1,2,3-Triazole; 2-Deoxy-2,3-dehydro-acetylneuraminic acid; Amino acid; Click chemistry; Sialic acid; Sialyltransferase inhibitors