1-脱氧野尻霉素与糖代谢酶相互作用的分子动力学计算
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摘要
1-脱氧野尻霉素(DNJ)是从桑叶中发现的一种天然生物碱,由于其结构与葡萄糖相似,可竞争性抑制糖苷酶活性,从而显著降低多糖的降解水平。本试验采用分子对接和分子动力学模拟方法,从PTP1B、PPARα、PPARγ、α-淀粉酶(α-Amylase)和α-葡萄糖苷酶(α-Glucosidase)等蛋白中确定了DNJ的作用靶标,并阐明其作用模式。结果表明,α-Glucosidase与DNJ的结合力有绝对优势,进一步的氢键分析和能量分解结果表明,Glu268、Asp330和Asp199是关键残基,在DNJ与α-葡萄糖苷酶结合中有重要作用,其作用方式是形成稳定的氢键作用,静电力作用和极性溶剂化能是主要的结合力来源。DNJ小分子通过与上述关键残基的作用稳定结合在α-葡萄糖苷酶口袋内部,从而抑制α-葡萄糖苷酶的生物活性,发挥降血糖作用。上述研究从分子结构层面阐明了DNJ和α-Glucosidase的作用模式,为基于DNJ结构进行理想药物的设计和小分子数据库的虚拟筛选提供了参考。
1-Deoxynojirimycin(DNJ) is a natural alkaloid found in mulberry leaf, which can significantly delay the degradation process of polysaccharides as a potent glycemic enzyme due to similar to the structure of glucose. This experiment identified the targets of DNJ and clarified their action models from PTP1 B, PPAR alpha, PPAR gamma, alpha Amylase(alpha Amylase) and alpha glycosidase enzymes(alpha-glucosidase) in protein by the molecular docking and molecular dynamics simulation method. The results showed that the alpha-glucosidase had absolute advantages to bind DNJ, further analysis of the hydrogen bond and the decomposition results showed that the Glu268, Asp330 and Asp199 were the key residues, which played an important role in the combination of DNJ and alpha Glucosidase. Its function was to form stable hydrogen bonds, and electrostatic force and polar solvation were the main sources of binding force. DNJ played the role of hypoglycemia by inhibiting the bioactivity of alpha glucosidase through combination with the above residues. The study illustrated the action mode of DNJ and alpha-glucosidase from the molecular structure level, which provided a clue to rational drug design and virtual screening of small molecule database based on the structure of DNJ.
1-Deoxynojirimycin(DNJ) is a natural alkaloid found in mulberry leaf, which can significantly delay the degradation process of polysaccharides as a potent glycemic enzyme due to similar to the structure of glucose. This experiment identified the targets of DNJ and clarified their action models from PTP1 B, PPAR alpha, PPAR gamma, alpha Amylase(alpha Amylase) and alpha glycosidase enzymes(alpha-glucosidase) in protein by the molecular docking and molecular dynamics simulation method. The results showed that the alpha-glucosidase had absolute advantages to bind DNJ, further analysis of the hydrogen bond and the decomposition results showed that the Glu268, Asp330 and Asp199 were the key residues, which played an important role in the combination of DNJ and alpha Glucosidase. Its function was to form stable hydrogen bonds, and electrostatic force and polar solvation were the main sources of binding force. DNJ played the role of hypoglycemia by inhibiting the bioactivity of alpha glucosidase through combination with the above residues. The study illustrated the action mode of DNJ and alpha-glucosidase from the molecular structure level, which provided a clue to rational drug design and virtual screening of small molecule database based on the structure of DNJ.
引文
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[2]邓玉玲,余璐,黄强.人类蛋白激酶组的多靶点分子对接系统[J].物理化学学报,2016,32(9):2355-2363DENG Yu-ling,YU Lu,HUANG Qiang.Multi-target molecular docking system of human protein kinase group[J].Journal of Physical Chemistry,2016,32(9):2355-2363
[3]刘冠辰.分子动力学模拟及在生物大分子模拟领域的应用[J].吉林化工学院学报,2015,11:112-116LIU Guan-chen.Molecular dynamics simulation and application in biomolecular simulation[J].Journal of Jilin University of Chemical Technology,2015,11:112-116
[4]Pettersen E F,Goddard T D,Huang C C,et al.UCSF Chimera-a visualization system for exploratory research and analysis[J].Journal of Computational Chemistry,2004,25(13):1605-1612
[5]Jakalian A,Bush B L,Jack D B,et al.Fast,efficient generation of high-quality atomic Charges.AM1-BCC model:I.Method[J].Journal of Computational Chemistry,2000,21(2):132-146
[6]Jakalian A,Jack D B,Bayly C I.Fast,efficient generation of high-quality atomic charges.AM1-BCC model:II.Parameterization and validation[J].Journal of Computational Chemistry,2002,23(16):1623-1641
[7]Lang P T,Brozell S R,Mukherjee S,et al.DOCK 6:Combining techniques to model RNA-small molecule complexes[J].Rna,2009,15(6):1219-1230
[8]Mukherjee S,Balius T E,Rizzo R C.Docking validation resources:protein family and ligand flexibility experiments[J].Journal of Chemical Information and Modeling,2010,50(11):1986-2000
[9]D A Case,J T Berryman,R M Betz,et al.Amber 2015,University of California,San Francisco,2015
[10]Jean-Paul Ryckaert,Giovanni Ciccotti,Herman J C Berendsen.Numerical integration of the cartesian equations of motion of a system withconstraints:Molecular dynamics of n-alkanes[J].Journal of Computational Physics,1977,23(3):327-341
[11]Tom Darden,Darrin York,Lee Pedersen.Particle mesh ewald:An nlog(n)method for ewald sums in large systems[J].Journal of Chemical Physics,1993,98
[12]Z H Yu,X Wen,Z Xi.Insight into herbicide resistance of W574L mutant Arabidopsis thaliana acetohydroxyacid synthase:molecular dynamics simulations and binding free energy calculations[J].Sci.China Chem.,2010,53(1):91-10