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首页> 外文期刊>International Journal of Biological Macromolecules: Structure, Function and Interactions >Novel GH-20 beta-N-acetylglucosaminidase inhibitors: Virtual screening, molecular docking, binding affinity, and anti-tumor activity
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Novel GH-20 beta-N-acetylglucosaminidase inhibitors: Virtual screening, molecular docking, binding affinity, and anti-tumor activity

机译：新型GH-20β-N-乙酰葡糖胺蛋白酶抑制剂：虚拟筛选，分子对接，结合亲和力和抗肿瘤活性

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摘要

beta-N-acetylglucosaminidases (GlcNAcases) play a crucial role in the metabolism of glycan-conjugated proteins/lipids in humans. Elevated levels of serum GlcNAcases have been associated with certain types of cancer, and GlcNAcases therefore serve as drug targets. Here, we employed virtual screening to identify two novel GlcNAcase inhibitors from the National Cancer Institute (NCI) Drug Library using a bacterial GH-20 GlcNAcase (VhGlcNAcase) as a search model. NSC73735 was shown to be most potent with IC50 of 12.7 +/- 1.2 mu M, agreeing with K-d of 0.94 +/- 0.2 mu M obtained by ITC. Molecular docking refinement indicated that Trp582 the key residue that interacted with all the inhibitor molecules. Docking NSC7373 into the active site of human O-GlcNAcase (hOGA) yielded reasonably good fit with the estimated K-d of 44.7 mu M, indicating its possibility to be a true binding partner. NSC73735 was shown to significantly suppress both cell growth and GlcNAcase activity of five cancer cell lines (U937, THP-1, MCF-7, HepG2 and PC-3) that express endogenous GlcNAcases. The cell cytotoxicity assay indicated the inherent effects of the lead compound on GlcNAcase expression with cancer cell proliferation, and therefore this novel GlcNAcase inhibitor may serve as a virtuous candidate for further development of highly potent antitumor agents. (C) 2019 Elsevier B.V. All rights reserved.
机译：β-n-乙酰葡糖胺酶（GlcNac酶）在人类甘草缀合的蛋白/脂质的代谢中起着至关重要的作用。血清GlcNacase的升高水平与某些类型的癌症有关，因此胶质酶作为药物靶标。在这里，我们使用虚拟筛查来使用细菌GH-20 GlcNac酶（VHGlcNace）作为搜索模型来鉴定来自国家癌症研究所（NCI）药物库的两种新的Glcnacase抑制剂。 NSC73735被证明是最有效的IC50，IC50为12.7 +/-1.2μm，同意ITC获得的0.94 +/-0.2μm的K-D。分子对接细化表明TRP582与所有抑制剂分子相互作用的关键残留物。将NSC7373放入人O-Glcnacase（Hoga）的活性位点，得到合理的合适，估计44.7μm的K-D，表明其成为真正的结合伴侣。显示NSC73735显着抑制了表达内源性GlcNac酶的五种癌细胞系（U937，THP-1，MCF-7，HepG2和PC-3）的细胞生长和Glcnacase活性。细胞细胞毒性测定表明铅化合物对具有癌细胞增殖的Glcnacase表达的固有作用，因此该新颖的GlcNac酶抑制剂可以作为进一步发展高效抗肿瘤剂的良性候选者。 （c）2019 Elsevier B.v.保留所有权利。

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