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

Abstract

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.

Structural Insights in Mammalian Sialyltransferases and Fucosyltransferases: We Have Come a Long Way, but It Is Still a Long Way Down

“…The SWISS-MODEL server has been used to generate a homology model of Hs ST3GAL1using the crystal structure of porcine ST3GAL [ 70 ]. Strecker et al used Schrodinger’s Maestro software to recreate a model of Hs FUT8 for donor substrate binding using its crystal structure [ 83 ]. In addition, a molecular dynamic (MD) simulation has been performed with Desmond v3 to explore the flexibility of Hs FUT8 [ 83 ].…”

“…Strecker et al used Schrodinger’s Maestro software to recreate a model of Hs FUT8 for donor substrate binding using its crystal structure [ 83 ]. In addition, a molecular dynamic (MD) simulation has been performed with Desmond v3 to explore the flexibility of Hs FUT8 [ 83 ]. Since both STs and FUTs are inverting glycosyltransferases that involve large conformational movements, we propose that the MD simulation techniques could be useful to study the flexible loops that are proposed in their catalysis.…”