Computation of relative binding free energy for an inhibitor and its analogs binding with Erk kinase using thermodynamic integration MD simulation | |
Kuan-Wei Wu; Po-Chin Chen; Jun Wang; Ying-Chieh Sun | |
2012-10 | |
发表期刊 | J Comput Aided Mol Des. |
卷号 | 26期号:10页码:1159-69 |
摘要 | In the present study, we carried out thermodynamic integration molecular dynamics simulation for a pair of analogous inhibitors binding with Erk kinase to investigate how computation performs in reproducing the relative binding free energy. The computation with BCC-AM1 charges for ligands gave −1.1 kcal/mol, deviated from experimental value of −2.3 kcal/mol by 1.2 kcal/mol, in good agreement with experimental result. The error of computed value was estimated to be 0.5 kcal/mol. To obtain convergence, switching vdw interaction on and off required approximately 10 times more CPU time than switching charges. Residue-based contributions and hydrogen bonding were analyzed and discussed. Furthermore, subsequent simulation using RESP charge for ligand gave ΔΔG of −1.6 kcal/mol. The computed results are better than the result of −5.6 kcal/mol estimated using PBSA method in a previous study. Based on these results, we further carried out computations to predict ΔΔG for five new analogs, focusing on placing polar and nonpolar functional groups at the meta site of benzene ring shown in the Fig. 1, to see if these ligands have better binding affinity than the above ligands. The computations resulted that a ligand with polar –OH group has better binding affinity than the previous examined ligand by ~2.0 kcal/mol and two other ligands have better affinity by ~1.0 kcal/mol. The predicted better inhibitors of this kind should be of interest to experimentalist for future experimental enzyme and/or cell assays. |
关键词 | Thermodynamic Integration – Md Simulation – Relative Binding Free Energy – Erk Kinase – Inhibitor |
学科领域 | 仿真与模拟 |
语种 | 英语 |
文献类型 | 期刊论文 |
条目标识符 | http://ir.qibebt.ac.cn/handle/337004/1321 |
专题 | 蛋白质设计研究组 |
推荐引用方式 GB/T 7714 | Kuan-Wei Wu,Po-Chin Chen,Jun Wang,et al. Computation of relative binding free energy for an inhibitor and its analogs binding with Erk kinase using thermodynamic integration MD simulation[J]. J Comput Aided Mol Des.,2012,26(10):1159-69. |
APA | Kuan-Wei Wu,Po-Chin Chen,Jun Wang,&Ying-Chieh Sun.(2012).Computation of relative binding free energy for an inhibitor and its analogs binding with Erk kinase using thermodynamic integration MD simulation.J Comput Aided Mol Des.,26(10),1159-69. |
MLA | Kuan-Wei Wu,et al."Computation of relative binding free energy for an inhibitor and its analogs binding with Erk kinase using thermodynamic integration MD simulation".J Comput Aided Mol Des. 26.10(2012):1159-69. |
条目包含的文件 | 下载所有文件 | |||||
文件名称/大小 | 文献类型 | 版本类型 | 开放类型 | 使用许可 | ||
Computation of relat(892KB) | 开放获取 | 使用许可 | 浏览 下载 |
除非特别说明,本系统中所有内容都受版权保护,并保留所有权利。
修改评论