1. Academic Validation
  2. Structure-based virtual screening and biological evaluation of novel non-bisphosphonate farnesyl pyrophosphate synthase inhibitors

Structure-based virtual screening and biological evaluation of novel non-bisphosphonate farnesyl pyrophosphate synthase inhibitors

  • Eur J Med Chem. 2020 Jan 15:186:111905. doi: 10.1016/j.ejmech.2019.111905.
Qingzhu Liu 1 Yinxing Miao 1 Xiaodan Wang 2 Gaochao Lv 1 Ying Peng 1 Ke Li 1 Ming Li 3 Ling Qiu 4 Jianguo Lin 5
Affiliations

Affiliations

  • 1 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, PR China.
  • 2 Wuxi Second Hospital Affiliated to Nanjing Medical University, Wuxi, 214002, PR China.
  • 3 State Key Laboratory of Animal Nutrition, Institute of Animal Science and Public Laboratory of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100081, PR China.
  • 4 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, PR China. Electronic address: qiuling@jsinm.org.
  • 5 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, PR China. Electronic address: linjianguo@jsinm.org.
Abstract

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 (KD = 14.3 ± 2.63 μM) 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 μM, respectively, whereas the IC50 value against FPPS low expressing MDA-MB-231 cells was >100 μM. 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.

Keywords

Anticancer drug; Farnesyl pyrophosphate synthase; Non-bisphosphonate inhibitor; Reactive oxygen species; Structure-based virtual screening.

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