CN105796559A - Zinc数据库中zinc19909927小分子在治疗肺腺癌的药中的应用 - Google Patents

Zinc数据库中zinc19909927小分子在治疗肺腺癌的药中的应用 Download PDF

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CN105796559A
CN105796559A CN201610300027.1A CN201610300027A CN105796559A CN 105796559 A CN105796559 A CN 105796559A CN 201610300027 A CN201610300027 A CN 201610300027A CN 105796559 A CN105796559 A CN 105796559A
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medicine
lung adenocarcinoma
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吴传芳
鲍锦库
万志宁
王海洋
孙荣
李鑫
王晓云
李建宗
王鑫
罗浩
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Sichuan University
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Abstract

本发明以ZINC数据库中ZINC19909927为材料，采用CCK8法检测ZINC19909927对肺腺癌细胞的杀伤效果，实验证明，ZINC19909927对肺腺癌细胞的增殖具有明显的抑制作用，为新型抗肿瘤药物的开发提供依据。

Description

ZINC 数据库中 ZINC19909927 小分子在治疗肺腺癌的药中的应用
技术领域
本发明属于医药技术领域，特别涉及ZINC19909927小分子在治疗肺腺癌的药中的应用。
背景技术
哺乳动物细胞供应能量有两种方式，线粒体氧化磷酸化和糖酵解。肿瘤细胞主要以糖酵解的方式获得能量以供应生长。与正常细胞相比，肿瘤细胞缺乏代谢灵活性，在缺氧和正常氧浓度条件下也维持糖酵解供能。糖酵解产生的ATP远不及线粒体氧化磷酸化，所以肿瘤细胞需要更多的葡萄糖[1-3]。对于葡萄糖的运输而言，因为葡萄糖是一种极性分子，它需要借助于细胞膜上的转运载体蛋白才能进入细胞内。GLUT1是在体内分布最为广泛的葡萄糖转运体，参与葡萄糖跨膜转运的正常生理过程。更为显著的是，GLUT1是葡萄糖吸收速率的限制型转运蛋白[4]。在很多癌细胞中，GLUT1的过量表达是一个普遍特征[5]。所以，GLUT1是治疗癌症的潜在靶点。研究者们已经开始研发抑制GLUT1的药物小分子，但由于GLUT1是膜转运蛋白，结构并不清晰，所以针对其结构的抑制剂研究还不显著。
在最近的研究中记录着几种GLUT1小分子抑制剂[6-8]。由于缺乏对GLUT1的晶体结构的了解，研究者们通常都是建立GLUT1的同源模拟模型来得出抑制剂结合位点。例如，虚拟分子对接研究显示Fasentin可与GLUT1内膜通道的一个特殊位点相互作用[6]。Perez A 发现Genistein可通过与GLUT1外表面结合改变葡萄糖与外表面结合位点[7]。此外，WZB117（位于GLUT1中心通道区域）可与蛋白质的氨基酸残基Asn34, Arg126和Trp412 形成三个氢键[8]。令人高兴的是，最新的研究表明已捕获到了GLUT1向内开放的晶体结构并确定了GLUT1的底物结合位点[9]。因此这使得开发一个新颖的有潜力的小分子抑制剂来竞争GLUT1的配体结合位点成为一个治疗癌症的有效策略。
随着人类基因组计划的完成和后续功能基因组（结构基因组、蛋白质组和代谢组等）的研究发展，形成了药物研究与开发的新思路和策略。生物信息学可以快速地分析、选择，协助人们从大量的数据中发现新作用的药物小分子，可以将含有潜在药物小分子的数据库和目标蛋白之间进行筛选。计算机辅助方法在小分子抑制剂合理设计中起到了重要作用[10,11]。我们利用计算机辅助药物设计的方法，设计出针对靶蛋白GLUT1向内构象分析的抑制剂。为此，我们使用了ZINC数据库中的specs子集数据库的32791个分子做虚拟筛选，这些化合物小分子的毒性测试结果是无害的。而基于片段药物设计的药物小分子化合物，还需要进一步进行毒性试验。我们节省了时间和金钱，进一步为药物的研发提供了便利。通过进一步数据整合分析，筛选得到ZINC19909927候选小分子。为了验证这个药物小分子在体外实验的效果，我们进行了初步的细胞毒性检测，发现药物小分子ZINC19909927能够有效地抑制A549肺腺癌细胞的体外增殖。
参考文献：
[1] Warburg O: On the origin of cancer cells. Science 1956, 123(3191):309-314.
[2] Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. science 2009, 324(5930):1029-1033.
[3] Hsu PP, Sabatini DM: Cancer cell metabolism: Warburg and beyond. Cell 2008, 134(5):703-707.
[4] Hatanaka M: Transport of sugars in tumor cell membranes. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 1974, 355(1):77-104.
[5] Medina RA, Owen GI: Glucose transporters: expression, regulation and cancer. Biological research 2002, 35(1):9-26.
[6] Wood TE, Dalili S, Simpson CD, Hurren R, Mao X, Saiz FS, Gronda M, Eberhard Y, Minden MD, Bilan PJ: A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death. Molecular Cancer Therapeutics 2008, 7(11):3546-3555.
[7] Pérez A, Ojeda P, Ojeda L, Salas Mn, Rivas CI, Vera JC, Reyes AM: Hexose transporter GLUT1 harbors several distinct regulatory binding sites for flavones and tyrphostins. Biochemistry 2011, 50(41):8834-8845.
[8] Liu Y, Zhang W, Cao Y, Liu Y, Bergmeier S, Chen X: Small compound inhibitors of basal glucose transport inhibit cell proliferation and induce apoptosis in cancer cells via glucose-deprivation-like mechanisms. Cancer letters 2010, 298(2):176-185.
[9] Deng D, Xu C, Sun P, Wu J, Yan C, Hu M, Yan N: Crystal structure of the human glucose transporter GLUT1. Nature 2014, 510(7503):121-125.
[10] Vacca JP, Condra JH: Clinically effective HIV-1 protease inhibitors. Drug Discovery Today 1997, 2(7):261-272.
[11] Blundell TL: Structure-based drug design. Nature 1996, 384:23-26。
发明内容
本发明的目的在于证明筛选得到的ZINC19909927小分子在治疗肺腺癌的药中的应用，为新型抗肿瘤药物的开发提供依据。
本发明通过实验证明：ZINC19909927具有抑制肺腺癌A549细胞增殖的作用。实验结果表明：
ZINC19909927对肺腺癌A549细胞的增殖抑制率与浓度和时间呈正相关性，其中，95 μM处理72h时达到最大抑制率74.17%。
本发明具有以下有益效果：
1、ZINC数据库中的子集数据库Specss中的ZINC19909927小分子的毒性测试结果是无害的。而基于片段药物设计的药物小分子化合物，还需要进一步进行毒性试验。我们节省了时间和金钱，进一步为药物的研发提供了便利。
2、本发明首次证明ZINC19909927小分子具有抑制肺腺癌细胞增殖的作用，为新型抗肿瘤药物的开发提供了新的思路。
3、ZINC19909927的抗肺腺癌活性也必将具有广阔的市场应用前景。
附表和附图说明
表1是本发明所述ZINC19909927对肺腺癌A549细胞生长的抑制效果。
图1是本发明所述ZINC19909927对肺腺癌A549细胞生长的抑制效果。
具体实施方式
实施例 1 ： ZINC19909927 小分子和试剂
化合物ZINC19909927购于ZINC数据库中ChemDiv。将ZINC19909927用PBS配置成储存液，使用时在培养基中稀释成0、5、20、35、50、65、80、95 μM/L浓度梯度；人肺腺癌细胞A549购自美国ATCC公司。RPMI 1640培养基购自ThermoFisher公司。 cell counting kit-8（CCK-8）试剂盒由碧云天提供。
实施例 2 ： A549 细胞培养
人肺腺癌A549细胞放于RPMI 1640培养基中培养，培养基中包含2.05 mM/L谷氨酰胺，10%的牛胎血清，1000μg/mL链霉素，10000 U/mL青霉素。A549细胞置于37℃、5％CO2 饱和湿度的细胞培养箱中培养。
实施例 3 ： CCK-8 法检测细胞毒性
将处于对数生长期的A549细胞接种于96孔板中，24 h后细胞已经完全贴壁，恢复到正常生长，分别加入含有不同浓度（0、5、20、35、50、65、80、95 μM/L）ZINC19909927的培养基继续孵育48 h、72 h，利用相差显微镜对细胞形态进行观察。对照组加入等体积的PBS孵育48 h、72 h。在酶标仪 450nm处读取 OD 值，并按下列公式计算细胞生长抑制率：细胞增殖抑制率（%）=1-{[A(加药)-A（空白）]/[A（0加药）-A（空白）]×100}。其中，A（加药）：具有细胞、CCK8溶液和药物溶液的孔的OD值；A（空白）：具有培养基和CCK8溶液而没有细胞的孔的OD值；A（0加药）：具有细胞、CCK8溶液而没有药物溶液的孔的OD值。
如表1和图1所示，ZINC19909927对肺腺癌A549细胞的增殖抑制率与浓度呈剂量时间依赖关系，其中，当小分子ZINC19909927浓度达到 95 μM处理72h时，A549细胞的增殖抑制几乎达到74.17%。
附表：
表1 ZINC19909927对肺腺癌A549细胞的生长抑制效果
。

Claims (1)

1.ZINC数据库中ZINC19909927小分子在治疗肺腺癌的药中的应用。
CN201610300027.1A 2016-05-09 2016-05-09 Zinc数据库中zinc19909927小分子在治疗肺腺癌的药中的应用 Pending CN105796559A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11940766B2 (en) 2018-07-25 2024-03-26 Ebs Sp. Z O.O. 3E Production Sp.K. Real estate monitoring system

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PAUL A. STEWART等: "A Pilot Proteogenomic Study with Data Integration Identifies MCT1 and GLUT1 as Prognostic Markers in Lung Adenocarcinoma", 《PLOS ONE》 *
Z. WAN等: "Computer-assisted identification of novel small molecule inhibitors targeting GLUT1", 《JOURNAL OF MOLECULAR STRUCTURE》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11940766B2 (en) 2018-07-25 2024-03-26 Ebs Sp. Z O.O. 3E Production Sp.K. Real estate monitoring system

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