青蒿素及其类似物抗疟构效关系的DFT研究
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摘要
为了从原子水平上揭示青蒿素及其类似物的结构与抗疟活性之间的关系,运用密度泛函理论DFT方法,在B3LYP/6-31G*水平上对青蒿素及其类似物二氢青蒿素、蒿甲醚和青蒿琥酯的结构和性质进行了理论计算。从分子的平衡构型、Wiberg键级、溶剂化能、偶极矩和静电势等方面分析了青蒿素及其类似物的抗疟构效关系。结果表明,青蒿素及其类似物结构中七元环上的过氧桥键、醚氧键以及六元环上的内酯结构是其抗疟作用的关键活性位,过氧桥键处负的静电势越多,青蒿素与血红素的相互作用越强,分子的抗疟活性越强。理论预测四个药物分子的抗疟活性顺序为:青蒿素<二氢青蒿素<蒿甲醚<青蒿琥酯,与实验活性结果一致。
In order to study the relationship between the structure and antimalarial activity of artemisinin and its analogues,the density functional theory( DFT) B3 LYP method with 6-31 G*basis set was used to calculate the geometries and properties of artemisinin and its analogues. The properties of the artemisinin and its analogues have been discussed in detail based on their molecular structures,Wiberg bond indexes,solvation energies,dipole moments and electrostatic potentials( ESPs). The results showed that the endoperoxy bridge on the seven-membered ring,the ether oxygen bond and six-member ring lactone structure were the most active sites for antimalarial activity of artemisinin and its analogues. The more negative electrostatic potential of the endoperoxy bridge,the stronger interaction between artemisinin and heme,and the stronger anti-malarial activity of the molecules would be. As a result,the order of antimalarial activity of the four drug molecules was predicted as: artemisinin
In order to study the relationship between the structure and antimalarial activity of artemisinin and its analogues,the density functional theory( DFT) B3 LYP method with 6-31 G*basis set was used to calculate the geometries and properties of artemisinin and its analogues. The properties of the artemisinin and its analogues have been discussed in detail based on their molecular structures,Wiberg bond indexes,solvation energies,dipole moments and electrostatic potentials( ESPs). The results showed that the endoperoxy bridge on the seven-membered ring,the ether oxygen bond and six-member ring lactone structure were the most active sites for antimalarial activity of artemisinin and its analogues. The more negative electrostatic potential of the endoperoxy bridge,the stronger interaction between artemisinin and heme,and the stronger anti-malarial activity of the molecules would be. As a result,the order of antimalarial activity of the four drug molecules was predicted as: artemisinin
引文
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18 Jiang HL,Chen KX,Wang HW,et al.Quantum chemical studies on antimalarial of artemisinin(qinghaosu)derivatives[J].Chin J Chem,1995,13:131-140.
19 Cheng F,Shen J,Luo X,et al.Molecular docking and 3D-QSAR studies on the possible antimalarial mechanism of artemisinin analogues[J].Bioorg Med Chem,2002,10:2883-2891.
20 Golenser J,Waknine JH,Krugliak M,et al.Current perspectives on the mechanism of action of artemisinins[J].Inter JParas,2006,36:1427-1441.
2 Chang ZY.The discovery of Qinghaosu(artemisinin)as an effective anti-malaria drug:a unique China story[J].Sci China Life Sci,2016,59:81-88.
3 White NJ.Qinghaosu(artemisinin):The price of success[J].Science,2008,320:330-334.
4 Institute of biophysics,Chinese academy of sciences,artemisinin group(中国科学院生物物理研究所青蒿素协作组).The crystal structure of artemisinin and its absolute configuration[J].Sci Chin(中国科学),1979,11:1114-1128.
5 Li Y,Yu PL,Cheng YX,et al.Synthesis of some derivatives of artemisinin[J].Chin Sci Bull(科学通报),1979,24:667-669.
6 Liang J,Li Y.Synthesis of the arylether derivatives of artemisinin[J].Chin J Med Chem(中国药物化学杂志),1996,19:22-25.
7 Liu X.Research of artemisinin derivatives[J].Chin Pharma Bull(药学通报),1980,15:183.
8 Guo Y,Wang J,Chen ZT.Recent advancement in pharmacological effects of artemisinin and its derivatives[J].Chin JClin Pharmacol Ther(中国临床药理学与治疗学),2006,11:615-620.
9 Li CC,Yin K,Yan G.Advances in research on the pharmacological action of the antimalarial artemisinin and its derivatives[J].J Patho Biol(中国病原生物杂志),2016,11:185-187.
10 Zhang N.Research progress of the artemisinin drugs[J].Chin J Drug Eval(中国药物评价),2013,30:13-16.
11 Li YX,Li XW,Nong XL.Review on anti-tumor mechanism and clinical application of artesunate[J].Nat Prod Res Dev(天然产物研究与开发),2016,28:986-989.
12 Zhou JY,Zhu Y.Progress in anti-tumor effects of artemisinin and its derivatives[J].Nat Prod Res Dev(天然产物研究与开发),2014,26:975-981.
13 Tomasi J,Persico M.Molecular interactions in solution:an overview of methods based on continuous distributions of the solvent[J].Chem Rev,1994,94:2027-2094.
14 Frisch MJ,Trucks GW,Schlegel HB,et al.Gaussian 16[CP].Revision A.01,Wallingford CT:Gaussian,Inc.,2016.
15 Lei JY,Chen Y,Feng XJ,et al.Electrostatic potentials of camptothecin and its analogues[J].Theor Chem Acc,2014,133:1-6.
16 Takeshi I.Ab initio quantum chemical calculation of electron density,electrostatic potential,and electric field of biomolecule based on fragment molecular orbital method[J].Int JQuantum Chem,2018,118:1-12.
17 Arpita V,Pradeep RV,Koichi Y,Do surfaces of positive electrostatic potential on different halogen derivatives in molecules attract?like attracting like[J].J Com Chem,2018,39:343-350.
18 Jiang HL,Chen KX,Wang HW,et al.Quantum chemical studies on antimalarial of artemisinin(qinghaosu)derivatives[J].Chin J Chem,1995,13:131-140.
19 Cheng F,Shen J,Luo X,et al.Molecular docking and 3D-QSAR studies on the possible antimalarial mechanism of artemisinin analogues[J].Bioorg Med Chem,2002,10:2883-2891.
20 Golenser J,Waknine JH,Krugliak M,et al.Current perspectives on the mechanism of action of artemisinins[J].Inter JParas,2006,36:1427-1441.