Identification of non-substrate-like glycosyltransferase inhibitors from library screening: pitfalls & hits†,RSC Medicinal Chemistry

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Identification of non-substrate-like glycosyltransferase inhibitors from library screening: pitfalls & hits†
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-11-29 00:00:00 , DOI: 10.1039/c7md00550d
Masaki Ema _{1,

2,

3,

4,

5} , Yong Xu _{1,

2,

3,

4,

5} , Sebastian Gehrke _{1,

5,

6,

7} , Gerd K. Wagner _{1,

2,

3,

4,

5}

Affiliation

Bacterial glycosyltransferases are potential targets for the development of novel antibiotics and anti-virulence agents. Most existing glycosyltransferase inhibitors are substrate analogues with limited potential for drug development. The identification of alternative inhibitor chemotypes is therefore of great interest for medicinal chemistry, drug discovery and chemical glycobiology. We describe the application of a biochemical glycosyltransferase assay to screen a small compound library containing three distinct chemical scaffolds (nucleosides, steroids and 5-methyl pyrazol-3-ones) against the retaining α-1,4-galactosyltransferase LgtC from Neisseria meningitidis. While no genuine LgtC inhibitory activity was observed in the nucleoside and steroid series, the best hit compounds in the 5-methyl pyrazol-3-one series showed low micromolar activity. We adapted our assay protocol to develop initial structure–activity relationships in this series, and to establish the target selectivity of the most potent inhibitor over two other glycosyltransferases. Our results provide insights into the activity of this class of non-substrate-like glycosyltransferase inhibitors, and highlight important general pitfalls for inhibitor screening against this enzyme family. Key elements of our experimental design, including a validated single-concentration protocol for inhibitor screening, and our process for elimination of false positives, are, in principle, directly transferable to many other sugar-nucleotide-dependent glycosyltransferases.

中文翻译：

从文库筛选中鉴定非底物样糖基转移酶抑制剂：陷阱和命中†

细菌糖基转移酶是开发新型抗生素和抗毒剂的潜在目标。大多数现存的糖基转移酶抑制剂是药物开发潜力有限的底物类似物。因此，对于药物化学，药物发现和化学糖生物学，鉴定替代抑制剂的化学型引起了极大的兴趣。我们描述了生化糖基转移酶测定法的应用，以筛选包含三个不同化学支架（核苷，类固醇和5-甲基吡唑-3-酮）的小化合物文库，用于对抗脑膜炎奈瑟氏球菌的保留α-1,4-半乳糖基转移酶LgtC。虽然在核苷和类固醇系列中未观察到真正的LgtC抑制活性，但在5-甲基吡唑-3-一系列中命中率最高的化合物显示出较低的微摩尔活性。我们调整了我们的测定方案，以开发该系列中的初始结构-活性关系，并建立了对两种其他糖基转移酶的最有效抑制剂的目标选择性。我们的结果提供了对这类非底物样糖基转移酶抑制剂的活性的见解，并强调了针对该酶家族进行抑制剂筛选的重要一般性陷阱。从理论上讲，我们的实验设计的关键要素，包括经过验证的用于抑制剂筛选的单一浓度方案，以及我们消除假阳性的流程，

更新日期：2017-11-29

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