In Silico Evaluation of the Binding Site of Fucosyltransferase 8 and First Attempts to Synthesize an Inhibitor with Drug-Like Properties

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  • Claas Strecker, University of Hamburg, Tyskland
  • Melissa Bärenfänger, University of Hamburg, Tyskland
  • Michaela Miehe
  • Edzard Spillner
  • Bernd Meyer, University of Hamburg, Tyskland
Core fucosylation of N‐glycans is catalyzed by fucosyltransferase 8 and is associated with various types of cancer. Most reported fucosyltransferase inhibitors contain non‐drug‐like features, such as charged groups. New starting points for the development of inhibitors of fucosyltransferase 8 using a fragment‐based strategy are presented. Firstly, we discuss the potential of a new putative binding site of fucosyltransferase 8 that, according to a molecular dynamics (MD) simulation, is made accessible by a significant motion of the SH3 domain. This might enable the design of completely new inhibitor types for fucosyltransferase 8. Secondly, we have performed a docking study targeting the donor binding site of fucosyltransferase 8, and this yielded two fragments that were linked and trimmed in silico. The resulting ligand was synthesized. Saturation transfer difference (STD) NMR confirmed binding of the ligand featuring a pyrazole core that mimics the guanine moiety. This ligand represents the first low‐molecular‐weight compound for the development of inhibitors of fucosyltransferase 8 with drug‐like properties.
OriginalsprogEngelsk
TidsskriftChemBioChem
Vol/bind21
Nummer13
Sider (fra-til)1923-1931
Antal sider9
ISSN1439-4227
DOI
StatusUdgivet - jul. 2020

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