|本期目录/Table of Contents|

[1]顾勇亮,董珂珂,王伟,等.DPP-4与氰基吡咯烷类抑制剂相互作用的分子动力学模拟[J].南京工业大学学报(自然科学版),2015,37(03):120-124.[doi:10.3969/j.issn.1671-7627.2015.03.022]
 GU Yongliang,DONG Keke,WANG Wei,et al.Molecular dynamics simulation of binding of cyanopyrrolidine inhibitors to dipeptidyl peptidase-4(DPP-4)[J].Journal of NANJING TECH UNIVERSITY(NATURAL SCIENCE EDITION),2015,37(03):120-124.[doi:10.3969/j.issn.1671-7627.2015.03.022]
点击复制

DPP-4与氰基吡咯烷类抑制剂相互作用的分子动力学模拟()
分享到:

《南京工业大学学报(自然科学版)》[ISSN:1671-7627/CN:32-1670/N]

卷:
37
期数:
2015年03期
页码:
120-124
栏目:
出版日期:
2015-05-30

文章信息/Info

Title:
Molecular dynamics simulation of binding of cyanopyrrolidine inhibitors to dipeptidyl peptidase-4(DPP-4)
文章编号:
1671-7627(2015)03-0120-05
作者:
顾勇亮董珂珂王伟朱小蕾
南京工业大学 化学化工学院 材料化学工程国家重点实验室,江苏 南京 210009
Author(s):
GU YongliangDONG KekeWANG WeiZHU Xiaolei
State Key Laboratory of Materials-Oriented Chemical Engineering,College of Chemistry and Chemical Engineering,Nanjing Tech University,Nanjing 210009,China
关键词:
分子动力学模拟 MM-PBSA方法 二肽基肽酶-4 氰基吡咯烷抑制剂
Keywords:
molecular dynamics simulation MM-PBSA method DPP-4 cyanopyrrolidine inhibitor
分类号:
O643.1
DOI:
10.3969/j.issn.1671-7627.2015.03.022
文献标志码:
A
摘要:
通过分子对接、分子动力学(MD)模拟和自由能分析的方法研究3种氰基吡咯烷抑制剂与二肽基肽酶-4(DPP-4)之间的成键机制,分析和讨论3种抑制剂与二肽基肽酶之间的静电相互作用、范德华相互作用。用MM-PBSA方法计算得到的3种抑制剂的结合自由能与实验测得的结果是一致的。抑制剂与残基所形成的氢键能够使抑制剂稳定在结合位点。由残基Tyr631和Tyr666与抑制剂形成的范德华相互作用对结合自由能起到关键作用,并且显著地将3种不同抑制剂的生物活性区分开来。
Abstract:
The binding mechanism between three cyanopyrrolidine inhibitors and DPP-4 was investigated by molecular docking,molecular dynamics(MD)simulation and binding free energy analysis.The electrostatic and van der Waals interactions of the three inhibitors with DPP-4 were analyzed and discussed.The computed binding free energies using MM-PBSA method were in qualitatively agreement with experimental inhibitory potency of three inhibitors.The hydrogen bonds of inhibitors could stabilize the inhibitors in binding sites.The van der Waals interactions,between the inhibitors and residue Tyr631 and Tyr666 showed the key contributions to the binding free energy and played an important role in distinguishing the variant bioactivity of three inhibitors.

参考文献/References:

[1] Stephen W,Mark J.Cis-2,5-dicyanopyrrolidine inhibitors of dipeptidyl peptidase IV:synthesis and in vitro,in vivo,and X-ray crystallographic characterization [J].Med Chem,2006,49:3068-3076.
[2] Nielsen L L.Incretin minetics and DPP-4 inhibitors for the treatment of type 2 diabetes[J].Drug Discov Today,2005,10(10):703-710.
[3] Nauck M A,Niedereichholz U,Ettler R,et al.Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulino-tropic effects in healthy humans[J].Am J Physiol,1997,273:E981-E988.
[4] Flint A,Raben A,Ersboll A K,et al.The effect of physiological levels of glucagons-like peptide-1 on appetite,gastric emptying,energy and substrate metabolism in obesity[J].Int J Obes Relat Metab Disord,2001,25:781-792.
[5] Ahren B.DPP-4 inhibitors[J].Best Prac Res Clin Endocrinol Metab,2007,21(4):517-533.
[6] Augeri D J,Robl J A,Betebenner D A,et al.Discovery and preclinical profile of saxagliptin(BMS-477118):a highly potent,long-acting,orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes[J].J Med Chem,2005,48(15):5025-5037.
[7] Villhauer E B,Brinkman J A,Naderi G B,et al.1-[[(3-hy-droxy-1-adamantyl)amino] acetyl] -2-cyano-(S)-pyrrolidine:a potent,selective,and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties[J].J Med Chem,2003,46(13):2774-2789.
[8] Kim D,Wang L,Beconi M,et al.(2R)-4-oxo-4-[3-(triflu-oromethyl)-5,6-dihydro[1,2,4] triazolo[4,3-a] pyrazin-7(8H)-yl] -1-(2,4,5-trifluorophenyl)butan-2-amine:a potent,orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes[J].J Med Chem,2005,48(1):141-151.
[9] Kuhn B,Hennig M,Mattei P.Molecular recognition of ligands in dipeptidyl peptidase IV[J].Curr Top Med Chem,2007,7(6):609-619.
[10] Weber A E.Dipeptidyl peptidase IV inhibitors for the treatment of diabetes[J].J Med Chem,2004,47(17):4135-4141.
[11] Case D A,Cheatham T A,Simmerling C L,et al.AMBER 10[M].San Francisco:University of California,2008.
[12] Wallace A C,Laskowski R A,Thornton J M.LIGPOLT:a program to generate schematic diagrams of protein-ligand interactions[J].Protein Eng,1995,8:127-134.
[13] Hu G D,Zhu T,Zhang S L,et al.Some insights into mechanism for binding and drug resistance of wild type and I50V V82A and I84V mutations in HIV-1 protease with GRL-98065 inhibitor from molecular dynamic simulations[J].Eur J Med Chem,2010,45:227-235.
[14] Wu E L,Han K,Zhang J Z.Selectivity of neutral/weakly basic P1 group inhibitors of thrombin and trypsin by a molecular dynamics study [J].Chem Eur J,2008,14:8704-8714.

相似文献/References:

[1]颜梦秋,杨晓宁.表面活性剂对CO2中表面润湿的分子动力学模拟[J].南京工业大学学报(自然科学版),2013,35(05):13.[doi:10.3969/j.issn.1671-7627.2013.05.003]
 YAN Mengqiu,YANG Xiaoning.Molecular dynamics simulation of effects of surfactant on surface wettability in CO2 environment[J].Journal of NANJING TECH UNIVERSITY(NATURAL SCIENCE EDITION),2013,35(03):13.[doi:10.3969/j.issn.1671-7627.2013.05.003]
[2](南京工业大学 化学化工学院 材料化学工程国家重点实验室,江苏 南京 0009).聚乙烯醇相变过程中的结构和物理性质的分子动力学模拟[J].南京工业大学学报(自然科学版),2015,37(02):12.
 GUAN Wenwen,WANG Jinjian,ZHU Xiaolei,et al.Molecular dynamics simulations on the structure and physical properties of polyvinyl alcohol during phase transition[J].Journal of NANJING TECH UNIVERSITY(NATURAL SCIENCE EDITION),2015,37(03):12.
[3]顾勇亮,董珂珂,王 伟,等.DPP-4与氰基吡咯烷类抑制剂相互作用的分子动力学模拟[J].南京工业大学学报(自然科学版),2015,37(03):12.
 GU Yongliang,DONG Keke,WANG Wei,et al.Molecular dynamics simulation of binding of cyanopyrrolidine inhibitors to DPP-4[J].Journal of NANJING TECH UNIVERSITY(NATURAL SCIENCE EDITION),2015,37(03):12.

备注/Memo

备注/Memo:
收稿日期:2014-03-14
基金项目:国家自然科学基金(21276122,21136001,20876073)
作者简介:顾勇亮(1988—),男,江苏南通人,硕士,主要研究方向为分子模拟; 朱小蕾(联系人),教授,E-mail:xlzhu@njtech.edu.cn.
引用本文:顾勇亮,董珂珂,王伟,等.DPP-4与氰基吡咯烷类抑制剂相互作用的分子动力学模拟[J].南京工业大学学报:自然科学版,2015,37(3):120-124..
更新日期/Last Update: 2015-05-20