α-葡萄糖苷酶抑制剂的虚拟筛选和分子动力学模拟
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- 英文论文题名：Virtual Screening and Molecular Dynamics Simulation of α-Glucosidase Inhibitors
- 论文作者：黄梦楠 ; 钟世钧
- 英文论文作者：Mengnan Huang ; Shijun Zhong ; School of Life Science and Biotechnology ; Dalian University of Technology
- 年：2016
- 作者机构：大连理工大学生命科学与技术学院;
- 论文关键词：α-葡萄糖苷酶 ; 虚拟筛选 ; 分子动力学模拟 ; 结合自由能 ; 抑制剂
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第十九分会：化学中的量子与经典动力学
- 语种：中文
- 分类号：TQ464.8
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第十九分会 ; 化学中的量子与经典动力学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：351k
- 原文格式：D
- 会议级别：全国
摘要
α-葡萄糖苷酶是在生物糖代谢过程中起关键作用的酶,主要参与糖类的分解。其竞争性抑制剂有助于减缓葡萄糖的生成速度,减缓肠道对葡萄糖的吸收,将餐后血糖浓度维持在正常水平,以此控制糖尿病以及并发症的发生。本文旨在通过分子对接、分子动力学模拟对其抑制剂进行虚拟筛选和构效关系研究。首先对ZINC数据库里的680多万个Leads进行虚拟筛选,受体为α-葡萄糖苷酶已报道的11种晶体结构模型,主要用到UCSF DOCK和LeDock等分子对接软件进行对接,通过一致性对接和一致性打分进行逐步筛选。同时用到pose scaling因子进行优化后,结合size归一化、聚类等筛选方法进行选择。对所选出的20个结合较好的小分子进行分子动力学模拟,计算结合自由能和氨基酸作用分解能,得到主要作用氨基酸及其结构特征,为非主要作用氨基酸的突变提供参考。通过结合自由能的比较,筛选出10个对α-葡萄糖苷酶有较好抑制活性的小分子化合物,得到抑制剂的结构特征和活性关系。
α-glucosidase plays a key role in the biological glucose metabolism, especially in the decomposition of carbohydrates. The competitive inhibitors assist to slow down the glucose production, and reduce the intestinal absorption of glucose, so that the postprandial blood glucose concentration can be maintained at a normal level. This paper aims at finding the inhibitors using virtual screening and molecular dynamics simulation. First, DOCK and LeDock were applied to 6.8 million leads of ZINC database, against the active site of α-glycosidase, using 11 crystal structure models, employing consensus scoring and consensus docking. The screening approach was further refined using the pose scaling, size normalization and clustering. The selected 20 molecules with better poses were subjected to molecular dynamics simulations and binding free energy calculation. In addition, the amino acid residues were analyzed for their structural characteristics and constructions to the ligand binding. Finally, 10 hits were suggested to experimental validation.
α-glucosidase plays a key role in the biological glucose metabolism, especially in the decomposition of carbohydrates. The competitive inhibitors assist to slow down the glucose production, and reduce the intestinal absorption of glucose, so that the postprandial blood glucose concentration can be maintained at a normal level. This paper aims at finding the inhibitors using virtual screening and molecular dynamics simulation. First, DOCK and LeDock were applied to 6.8 million leads of ZINC database, against the active site of α-glycosidase, using 11 crystal structure models, employing consensus scoring and consensus docking. The screening approach was further refined using the pose scaling, size normalization and clustering. The selected 20 molecules with better poses were subjected to molecular dynamics simulations and binding free energy calculation. In addition, the amino acid residues were analyzed for their structural characteristics and constructions to the ligand binding. Finally, 10 hits were suggested to experimental validation.
引文
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[2]Starzec,A.;Miteva,M.A.;Ladam,P.Bioorganic&medicinal chemistry.2014,22(15):4042-4048.
[3]Zhao,H.;Caflisch,A.Bioorganic&medicinal chemistry letters,2013,23(20):5721-5726.
[4]Zhong,S.;Zhang,Y.;Xiu,Z.Curr Opin Drug Discov Devel,2010,13(3):326-334.