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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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In Silico Evaluation of the Binding Site of Fucosyltransferase 8 and First Attempts to Synthesize an Inhibitor with Drug-Like Properties. / Strecker, Claas; Bärenfänger, Melissa; Miehe, Michaela; Spillner, Edzard; Meyer, Bernd.

I: ChemBioChem, Bind 21, Nr. 13, 07.2020, s. 1923-1931.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{b463ab4fc2084300a09c32e712254e39,
title = "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.",
keywords = "fragment-based drug discovery, fucosyltransferase 8, glycosylation, glycosyltransferase inhibitors, molecular modeling, FUT8, ALPHA-1,6-FUCOSYL-TRANSFERASE, DISCOVERY, ZINC",
author = "Claas Strecker and Melissa B{\"a}renf{\"a}nger and Michaela Miehe and Edzard Spillner and Bernd Meyer",
year = "2020",
month = jul,
doi = "10.1002/cbic.201900289",
language = "English",
volume = "21",
pages = "1923--1931",
journal = "ChemBioChem",
issn = "1439-4227",
publisher = "Wiley - V C H Verlag GmbH & Co. KGaA",
number = "13",

}

RIS

TY - JOUR

T1 - In Silico Evaluation of the Binding Site of Fucosyltransferase 8 and First Attempts to Synthesize an Inhibitor with Drug-Like Properties

AU - Strecker, Claas

AU - Bärenfänger, Melissa

AU - Miehe, Michaela

AU - Spillner, Edzard

AU - Meyer, Bernd

PY - 2020/7

Y1 - 2020/7

N2 - 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.

AB - 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.

KW - fragment-based drug discovery

KW - fucosyltransferase 8

KW - glycosylation

KW - glycosyltransferase inhibitors

KW - molecular modeling

KW - FUT8

KW - ALPHA-1,6-FUCOSYL-TRANSFERASE

KW - DISCOVERY

KW - ZINC

U2 - 10.1002/cbic.201900289

DO - 10.1002/cbic.201900289

M3 - Journal article

C2 - 31194280

VL - 21

SP - 1923

EP - 1931

JO - ChemBioChem

JF - ChemBioChem

SN - 1439-4227

IS - 13

ER -