Possible ligand release pathway of dipeptidyl peptidase IV investigated by molecular dynamics simulations
Possible ligand release pathway of dipeptidyl peptidase IV investigated by molecular dynamics simulations
复制标题
DOI：
10.1002/prot.23004
复制
发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Cui Li;Jie Shen;Weihua Li;Chunhua Lu;Guixia Liu;Yun Tang
中科院分区：
文献类型：
--
作者：
Cui Li;Jie Shen;Weihua Li;Chunhua Lu;Guixia Liu;Yun Tang
二肽基肽酶4(DPP4)是治疗II型糖尿病的重要靶点。DPP4的晶体结构表明，有两条可能的途径到达活性中心，即侧面开口和β螺旋桨开口。然而，目前还缺乏定量的证据来说明哪种途径更有利于抑制剂进入或释放出活性部位。在这项研究中，通过常规的和转向的分子动力学模拟来探索抑制剂Q448从DPP4的活性部位通过这两条可能的途径释放的细节。作用力和功与平均作用力势的比较结果表明，侧向开孔可能更有利于缓蚀剂通过。此外，Glu205-Glu206和Phe357被认为是抑制剂结合活性部位的两个关键残基。在此基础上，提出了进一步设计缓蚀剂的建议。蛋白质2011；©2011 Wiley-Liss，Inc.
Dipeptidyl peptidase IV (DPP4) is an important target for the treatment of Type II diabetes mellitus. The crystal structure of DPP4 demonstrates that there are two possible pathways to the active site, a side opening and a β propeller opening. However, it still lacks quantitative evidence to illustrate which pathway is more favorable for inhibitor to enter into or release from the active site. In this study, conventional and steered molecular dynamics simulations were performed to explore the details of inhibitor Q448 release from the active site of DPP4 via the two potential pathways. The comparisons of force and work together with potentials of mean force results suggested that the side opening might be more favorable for the inhibitor to pass through. Moreover, Glu205‐Glu206 and Phe357 were recognized as two “key residues” in the active site for inhibitor binding. Accordingly, suggestions for further inhibitor design wereprovided. Proteins 2011; © 2011 Wiley‐Liss, Inc.