文献类型：期刊文献

英文题名：Discovery of Natural Products Targeting NQO1 via an Approach Combining Network-Based Inference and Identification of Privileged Substructures

作者：Wu, Zengrui[1];Wang, Qiaohui[1,2];Yang, Hongbin[1];Wang, Jiye[1];Li, Weihua[1];Liu, Guixia[1];Yang, Yi[2,3];Zhao, Yuzheng[1,2];Tang, Yun[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Optogenet & Synthet Biol Interdisciplinary Res Ct, Shanghai Collaborat Innovat Ctr Biomfg Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[3]Chinese Acad Sci, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci, Shanghai 200031, Peoples R China

年份：2021

卷号：61

期号：5

起止页码：2486

外文期刊名：JOURNAL OF CHEMICAL INFORMATION AND MODELING

收录：;EI(收录号：20212210415861);WOS:【SCI-EXPANDED(收录号:WOS:000656118800034)】；

基金：This work was supported by the National Key Research and Development Program of China (grants 2016YFA0502304 and 2019YFA0904800), the National Natural Science Foundation of China (grants 81673356 and 81872800), the Shanghai Postdoctoral Excellence Program (grant 2018199), the Shanghai Sailing Program (grant 19YF1412700), the China Postdoctoral Science Foundation (grant 2019M661413), and the 111 Project (grant BP0719034).

语种：英文

外文关键词：Neurodegenerative diseases - Quinone

摘要：NAD(P)H:quinone oxidoreductase 1 (NQO1) has been shown to be a potential therapeutic target for various human diseases, such as cancer and neurodegenerative disorders. Recent advances in computational methods, especially network-based methods, have made it possible to identify novel compounds for a target with high efficiency and low cost. In this study, we designed a workflow combining network-based methods and identification of privileged substructures to discover new compounds targeting NQO1 from a natural product library. According to the prediction results, we purchased 56 compounds for experimental validation. Without the assistance of privileged substructures, 31 compounds (31/56 = 55.4%) showed IC50 < 100 mu M, and 11 compounds (11/56 = 19.6%) showed IC50 < 10 mu M. With the assistance of privileged substructures, the two success rates were increased to 61.8 and 26.5%, respectively. Seven natural products further showed inhibitory activity on NQO1 at the cellular level, which may serve as lead compounds for further development. Moreover, network analysis revealed that osthole may exert anticancer effects against multiple cancer types by inhibiting not only carbonic anhydrases IX and XII but also NQO1. Our workflow and computational methods can be easily applied in other targets and become useful tools in drug discovery and development.