基于配体与受体结构的酪氨酸酶抑制剂定量构效关系分析

doi:10.11944/j.issn.1000-0518.2018.07.170332

摘要/Abstract

摘要：

酪氨酸酶是细胞内催化合成黑素的关键酶。理解酪氨酸酶抑制剂结构与活性之间的关系对于设计新药和化妆品具有重要意义。然而,酪氨酸酶抑制剂的定量构效关系仍不清楚。本文利用配体和结构描述符构建了隐式和显式模型,阐明了酪氨酸酶抑制剂定量构效关系。隐式模型的相关系数R高达0.961,显式模型的相关系数为0.775。两个模型很好地预测了3个茶多酚的酪氨酸酶抑制活性,表儿茶素没食子酸酯(ECG)>表没食子儿茶素没食子酸酯(EGCG)>没食子酸(G)。相关性分析发现,抑制剂与酪氨酸酶结合引起的构象熵损失与抑制剂的活性密切相关。具有较少构象熵损失的ECG在4种茶多酚中具有较高酪氨酸酶抑制活性。结合自由能计算也证实ECG与酪氨酸酶的结合能力最强。此外,通过分解结合自由能发现,酪氨酸酶活性中心的氨基酸残基(His57、His201、Asn202、His205、Glu192和Val215)与抑制剂形成了较强的范德华和静电相互作用,进而稳定了复合物结构。

关键词: 酪氨酸酶, 定量构效关系, 分子力学-Poisson Boltzmann表面积方法, 随机森林, 蒙特卡罗

Abstract:

The use of variant inhibitors to regulate the bioactivities of tyrosinase, which is the key enzyme in charge of the production of melanin and pigments, is a long-standing approach to design cosmetic and pharmaceutical products. The quantitative description of the structure-activity relationship of tyrosinase inhibitors is still unclear. In this study, we constructed descriptive models by integrating ligand- and structure-based approaches for such purpose. They provide correlation coefficients of 0.961 for implicit models and 0.775 for explicit model, respectively, to descript the activities of three tea polyphenols with the tyrosinase inhibitory activity order of (-)-Epicatechin gallate(ECG)>(-)-Epigallocatechin gallate(EGCG)>Gallic acid(G). As revealing from the descriptive models, entropy loss is more important than other features for determining inhibitory activity and thus the tyrosinase-ECG complex with the fewer conformational entropy loss has the strongest inhibitory activity in vitro among the four tea polyphenols. Moreover, residues including His57, His201, Asn202, His205 Glu192 and Val215 are the core of active sites in tyrosinase, and stabilize the tyrosinase-inhibitor complex by van der Waals and hydrogen bonding interactions.

Key words: tyrosinase, quantitative structure-activity relationship, molecular mechanics/Poisson Boltzmann surface area, Random Forest algorithm, Monte Carlo algorithm

汤海峰,崔凤超,刘伦洋,李云琦. 基于配体与受体结构的酪氨酸酶抑制剂定量构效关系分析[J]. 应用化学, 2018, 35(7): 788-794.

Haifeng TANG,Fengchao CUI,Lunyang LIU,Yunqi LI. Insight into the Inhibitory Activities of Diverse Ligands for Tyrosinase Using Ligand- and Structure-based Approaches[J]. Chinese Journal of Applied Chemistry, 2018, 35(7): 788-794.

参考文献

[1]	ZHENG Aping,CHEN Bingnian,CHEN Fahe,et al. Inhibition Effect of Vanadate-Replaced Polyoxometalates on Mushroom Tyrosinase[J]. Chinese J Appl Chem,2013,30(2):165-170(in Chinese). 郑阿萍,陈丙年,陈发河,等. 钒取代硅钨氧酸盐对酪氨酸酶的抑制作用[J]. 应用化学,2013,30(2):165-170.
[2]	Kubo I,Chen Q,Nihei K.Molecular Design of Antibrowning Agents:Antioxidative Tyrosinase Inhibitors[J]. Food Chem,2003,81(2):241-247.
[3]	Yi W,Cao R,Peng W,et al. Synthesis and Biological Evaluation of Novel 4-Hydroxybenzaldehyde Derivatives as Tyrosinase Inhibitors[J]. Eur J Med Chem,2010,45(2):639-646.
[4]	LI Lili,CHEN Bingnian,DENG Yangyang,et al. Inhibitory Effects of Dawson Type Polyoxometalates on Tyrosinase[J]. Chinese J Appl Chem,2017,34(1):83-89(in Chinese). 李莉莉,陈丙年,邓阳阳,等. Dawson 结构的多金属氧酸盐对酪氨酸酶的抑制作用[J]. 应用化学,2017,34(1):83-89.
[5]	WANG Zhen,DONG Wei,XU Yan,et al. Synthesis of Substituted Benzylidene Hydrazinecarbothioamide(Hydrazinecarboxamide, Nitrohydrazinecarboximidamide) and Their Inhibitory Activity on Tyrosinase of Diamondback Moth Plutella xylostella(L.)[J]. Chinese J Pestic Sci,2010,12(3):264-268(in Chinese). 王振,董炜,徐焱,等. 取代苯甲醛缩氨基硫脲_脲_硝基胍_类化合物的合成及其对小菜蛾酪氨酸酶的抑制活性[J]. 农药药学报,2010,12(3):264-268
[6]	Chai W,Shi Y,Feng H,et al. Structure Characterization and Anti-Tyrosinase Mechanism of Polymeric Proanthocyanidins Fractionated from Kiwifruit Pericarp[J]. J Agric Food Chem,2014,62(27):6382-6389.
[7]	Le-Thi-Thu H,Casanola-Martin G M,Marrero-Ponce Y,et al. Novel Coumarin-Based Tyrosinase Inhibitors Discovered by OECD Principles-Validated QSAR Approach from an Enlarged, Balanced Database[J]. Mol Diversity,2011,15(2):507-520.
[8]	Caldas G B,Ramalho T C,da Cunha E F F. Application of 4D-QSAR Studies to a Series of Benzothiophene Analogs[J]. J Mol Model,2014,20:2420.
[9]	Ai N,Welsh W J,Santhanam U,et al. Novel Virtual Screening Approach for the Discovery of Human Tyrosinase Inhibitors[J]. PloS One,2014,9(11):e112788.
[10]	Azam S S,Uddin R,Syed A A S,et al. Molecular Docking Studies of Potent Inhibitors of Tyrosinase and α-Glucosidase[J]. Med Chem Res,2012,21(8):1677-1683.
[11]	de la Lande A,Maddaluno J,Parisel O,et al. Study of the Docking of Competitive Inhibitors at a Model of Tyrosinase Active Site:Insights from Joint Broken-Symmetry/Spin-Flip DFT Computations and ELF Topological Analysis[J]. Interdisciplin Sci-Comput Life Sci,2010,2(1):3-11.
[12]	Piquemal J,Maddaluno J,Silvi B,et al. Theoretical Study of Phenol and 2-Aminophenol Docking at a Model of the Tyrosinase Active Site[J]. New J Chem,2003,27(6):909-913.
[13]	Takahashi S,Kamiya T,Saeki K,et al. Structural Insights into the Hot Spot Amino Acid Residues of Mushroom Tyrosinase for the Bindings of Thujaplicins[J]. Biorg Med Chem,2010,18(22):8112-8118.
[14]	Kang S,Heo S,Kim K,et al. Molecular Docking Studies of a Phlorotannin, Dieckol Isolated from Ecklonia Cava with Tyrosinase Inhibitory Activity[J]. Biorg Med Chem,2012,20(1):311-316.
[15]	Seebeck B,Reulecke I,Kaemper A,et al. Modeling of Metal Interaction Geometries for Protein-Ligand Docking[J]. Proteins:Struct Funct Bioinf,2008,71(3):1237-1254.
[16]	Kolbe L,Mann T,Gerwat W,et al. 4-N-Butylresorcinol, a Highly Effective Tyrosinase Inhibitor for the Topical Treatment of Hyperpigmentation[J]. J Eur Acad Dermatol Venereol,2013,27:19-23.
[17]	Curto E V,Kwong C,Hermersdorfer H,et al. Inhibitors of Mammalian Melanocyte Tyrosinase:In Vitro Comparisons of Alkyl Esters of Gentisic Acid with Other Putative Inhibitors[J]. Biochem Pharmacol,1999,57(6):663-672.
[18]	Breiman L.Random Forests[J]. Mach Learn,2001,45(1):5-32.
[19]	Li Y,Fang J.PROTS-RF:A Robust Model for Predicting Mutation-Induced Protein Stability Changes[J]. PLoS One,2012,7(10):e47247.
[20]	Li Y,Zhang J,Tai D,et al. PROTS:A Fragment Based Protein Thermo-Stability Potential[J]. Proteins:Struct,Funct Bioinf,2012,80(1):81-92.
[21]	Becke A D.Density-Functional Exchange-Energy Approximation with Correct Asymptotic-Behavior[J]. Phys Rev A,1988,38(6):3098-3100.
[22]	Xue C,Luo W,Ding Q,et al. Quantitative Structure-Activity Relationship Studies of Mushroom Tyrosinase Inhibitors[J]. J Comput Aided Mol Des,2008,22(5):299-309.
[23]	Berman H M,Westbrook J,Feng Z,et al. The Protein Data Bank[J]. Nucl Acids Res,2000,28(1):235-242.
[24]	Phillips J C,Braun R,Wang W,et al. Scalable Molecular Dynamics with NAMD[J]. J Comput Chem,2005,26(16):1781-1802.
[25]	Srinivasan J,Cheatham T E,Cieplak P,et al. Continuum Solvent Studies of the Stability of DNA, RNA, and Phosphoramidate-DNA Helices[J]. J Am Chem Soc,1998,120(37):9401-9409.
[26]	Case D A,Darden T A,Cheatham T E,et al. Amber 12,2012.
[27]	Miller B R,McGee T D,Jr,Swails J M,et al.MMPBAS.Py:An Efficient Program for End-State Free Energy Calculations[J]. J Chem Theory Comput,2012,8(9):3314-3321.
[28]	Cui F,Yang K,Li Y.Investigate the Binding of Catechins to Trypsin Using Docking and Molecular Dynamics Simulation[J]. PloS One,2015,10(5):5994-5998.
[29]	Jeong S H,Ryu Y B,Curtis-Long M J,et al. Tyrosinase Inhibitory Polyphenols from Roots of Morus Ihou[J]. J Agric Food Chem,2009,57(4):1195-1203.
[30]	Munoz E,Avila J G,Alarcon J,et al. Tyrosinase Inhibitors from Calceolaria integrifolia s.l.:Calceolaria talcana Aerial Parts[J]. J Agric Food Chem,2013,61(18):4336-4343.
[31]	Kier L B,Hall L H.An Electrotopological-State Index for Atoms in Molecules[J]. Pharm Res,1990,7(8):801-807.
[32]	LI Lili,CHEN Bingnian,DENG Yangyang,et al. Inhibitory Effects of Dawson Type Polyoxometalates on Tyrosinase[J]. Chinese J Appl Chem,2017,34(1):83-89(in Chinese). 李莉莉,陈丙年,邓阳阳,等. Dawson结构的多金属氧酸盐对酪氨酸酶的抑制作用[J]. 应用化学,2017,34(1):83-89.
[33]	Xing R,Zheng A,Wang F,et al. The Inhibitory Mechanism Research of Vanadate-Substituted Polyoxometalates on Tyrosianse[J]. J Mol Sci,2015,31(5):436-440.
[34]	Tse M,Kermasha S,Ismail A.Biocatalysis by Tyrosinase in Organic Solvent Media; A Model System Using Catechin and Vanillin as Substrates[J]. J Mol Catal B-Enzym,1997,2(4/5):199-213.
[35]	Kermasha S,Bao H,Bisakowski B.Biocatalysis of Tyrosinase Using Catechin as Substrate in Selected Organic Solvent Media[J].J Mol Catal B-Enzym,11(4/5/6):929-938.