Glycosyltransferases (GTs) are enzymes involved in the biosynthesis of oligosaccharides, polysaccharides and glycoconjugates. Modulation of GTs activities by efficient inhibitors is promising for the control of various molecular recognition processes including bacterial and viral infections. Therefore selective inhibitors of GTs are of interest because they may lead to the development of novel therapeutic agents [1]. Identification of potent inhibitors has been developing very rapidly during the last two decades since the 3D structures of several GTs were found [2] and catalytic mechanism proposed [3].

The use of computer-aided structure-based approach has been very useful for the optimization and de novo discovering inhibitors of enzymes. As a rational design of lead compounds this report focused on the investigation of an interaction between 2-deoxy sugar derivatives of uridine and active site of target proteins, GnT I and GalT I. The ligand-protein interactions were simulated with a docking GOLD 3.2 software [4]. A small but diverse library containing 28 ligands was assembled. Structures in the set possessed common uridine motif and two moieties of 2-deoxy sugar connected by α-(1→3)-, α-(1→4)- or α-(1→6)-linked glycosidic linkages and can be synthesized in a totally stereoselective manner [5]. Uridine fragment is supposed to ensure reasonable interactions with enzyme, similar to that of natural substrate. All ligands were docked into the active sites of target proteins and the bound conformations inside the active sites were visually examined. Visual analysis of the ligand-protein complexes as well as the scores from docking simulations suggest that some structures bind the enzymes active sites by a similar mode as their natural substrates. Selected compounds will be synthesized and subjected to bioactivity assays in traditional enzymatic tests.

Acknowledgement

Financial support from The Polish State Committee for Scientific Research (Grant No. 1 T09 A 08630) and The Board of Faculty of Chemistry (Grant BW-RCh-2/2008) are gratefully acknowledged.

[1] K. H. Jung, R. R. Schmidt Glycosylotransferase Inhibitors in: “Carbohydrate–Based Drug Discovery”, C.–H. Wong (Ed.), Wiley – VCH, ch. 2, 609–659 (2003).
[2] C. Breton, L. Šnajdrowa, C. Jeanneau, J. Koča, A. Imberty, Glycobiology 16 (2006) 29R-37R.
[3] I. Tvoroška, I. André, J. P. Carver, J. Am. Chem. Soc. 122 (2000) 8762-8776.
[4] G. Jones, P. Wilett, R. C. Glein, A. R. Leach, R. Taylor, J. Mol. Biol., 267 (1997) 727-748.
[5] I. Wandzik, T. Bieg, Bioorg. Chem., 35 (2007) 401-416.

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