数字农科院2.0

Structure-Based Virtual Screening And Biological Evaluation Of Novel Non-Bisphosphonate Farnesyl Pyrophosphate Synthase Inhibitors

文献类型： 外文期刊

作者： Liu, QZ; Miao, YX; Wang, XD; Lv, GC; Peng, Y; Li, K; Li, M; Qiu, L; Lin, JG

作者机构：

关键词： Farnesyl Pyrophosphate Synthase; Structure-Based Virtual Screening; Non-Bisphosphonate Inhibitor; Anticancer Drug; Reactive Oxygen Species

期刊名称： EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

ISSN： 0223-5234

年卷期： 2020 年 186 卷

页码：

收录情况： JCR（2021版）

摘要： Farnesyl pyrophosphate synthase (FPPS) is known to participate in a variety of disease-related cell signaling pathway and bisphosphonates (BPs) are served as FPPS inhibitors. However, the high polarity of BPs often induces a series of side effects, limiting their applications. In the present study, novel non-BP FPPS inhibitors were discovered by in silico screening and experimental validation. From the structure-based virtual screening (SBVS) strategy combining molecular docking, pharmacophore and binding affinity prediction, 10 hits with novel scaffolds were filtered. The inhibition activity of hits against FPPS was identified and 7 hits showed comparable or higher inhibition activity than Zoledronate. The hit VS-4 with higher lipophilicity (XlogP = 1.81) and binding affinity (K-D = 14.3 +/- 2.63 mu M) to FPPS was selected for further study on cancer cells with different FPPS expression level. Experimental results revealed that VS-4 could better target the FPPS high-expressing colon LoVo and HCT116 cancer cell lines with IC50 of 51.772 +/- 0.473 and 43.553 +/- 1.027 mu M, respectively, whereas the IC50 value against FPPS low expressing MDA-MB-231 cells was >100 mu M. The mechanism of VS-4 against colon cancer cells was investigated by flow cytometry and the results indicated that VS-4 induced cell apoptosis by increasing the intracellular reactive oxygen species (ROS) level. Taken together, the SBVS strategy could be used to discover promising non-BP FPPS inhibitors and the lead compound VS-4 might shed a light on designing more potent inhibitors as novel anticancer drugs. (C) 2019 Elsevier Masson SAS. All rights reserved.

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