Discovery of Novel Inhibitors Targeting Human O-GlcNAcase: Docking-Based Virtual Screening, Biological Evaluation, Structural Modification, and Molecular Dynamics Simulation

文献类型： 外文期刊

第一作者： Dong, Lili

作者： Dong, Lili;Shen, Shengqiang;Xu, Dongdong;Lu, Huizhe;Zhang, Jianjun;Chen, Wei;Yang, Qing

作者机构：

期刊名称：JOURNAL OF CHEMICAL INFORMATION AND MODELING （ 影响因子：4.956； 五年影响因子：5.39 ）

ISSN： 1549-9596

年卷期： 2019 年 59 卷 10 期

页码：

收录情况： SCI

摘要： beta-N-Acetylhexosaminidases have emerged as promising targets for drug and pesticide discovery due to their critical physiological functions in various cellular processes. In particular, human O-GlcNAcase (hOGA) from the glycoside hydrolase family 84 (GH84) has gained significant attention. This enzyme was found to be linked to various diseases such as diabetes, cancer, and Alzheimer's disease (AD). In this study, to develop novel hOGA inhibitors with suitable pharmaceutical properties, virtual screening of the Drugbank database was performed using a docking-based approach targeting hOGA. Chlorhexidine (4, K-i = 4.0 mu M) was identified as a potent hOGA inhibitor with excellent selectivity (K-i > 200 mu M against human beta-N-acetylhexosaminidase B) and subjected to structural modifications and SAR studies. Furthermore, molecular dynamics simulations as well as binding free energy and free energy decomposition calculations were carried out to investigate the basis for the efficiency of potent inhibitors against hOGA. This present work revealed the new application of the disinfectant Chlorhexidine and provided useful information for the future design of hOGA inhibitors.

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