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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Structure-based virtual screening and biological evaluation of novel non-bisphosphonate farnesyl pyrophosphate synthase inhibitors
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Structure-based virtual screening and biological evaluation of novel non-bisphosphonate farnesyl pyrophosphate synthase inhibitors

机译：基于结构的虚拟筛选和新型非双膦酸盐法呢基焦磷酸盐合酶抑制剂的生物学评价

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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.
机译：已知法牛糖焦磷酸盐合酶（FPP）参与各种疾病相关的细胞信号传导途径，并且双膦酸盐（BPS）用作FPPS抑制剂。然而，BPS的高极性通常诱导一系列副作用，限制了它们的应用。在本研究中，在硅筛选和实验验证中发现了新的非BP FPPS抑制剂。从基于结构的虚拟筛选（SBV）策略结合分子对接，药物团和结合亲和力预测，过滤了新的支架10次次次次次次。鉴定了对FPPS的命中的抑制活性，并且7次命中显示比唑妥替纳酸盐相当或更高的抑制活性。选择具有更高亲脂性（XLogP = 1.81）的HET VS-4和结合亲和力（K-D = 14.3 +/-2.63μm）以进一步研究具有不同FPPS表达水平的癌细胞。实验结果表明，VS-4分别可以更好地靶向FPPS高表达的冒号LOVO和HCT116癌细胞系，分别使用IC50为51.772 +/- 0.473和43.553 +/- 1.027 mu m，而IC50对FPPS低表达MDA的值通过流式细胞术研究-MB-231细胞>100μm。通过流式细胞术研究VS-4对结肠癌细胞的机制，结果表明，通过增加细胞内反应性氧（ROS）水平，VS-4诱导细胞凋亡。占据了SBVS策略可用于发现有前途的非BP FPPS抑制剂，并且铅化合物VS-4可能揭示了设计更有效的抑制剂作为新型抗癌药物。 （c）2019年Elsevier Masson SAS。版权所有。

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