Studies of chirality effect of 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine on p38 alpha by molecular dynamics simulations and free energy calculations
文献类型：期刊论文
| 作者 | Chen, Quan; Cui, Wei; Ji, Mingjuan |
| 刊名 | Journal of computer-aided molecular design
 |
| 出版日期 | 2009-10-01 |
| 卷号 | 23期号:10页码:737-745 |
| ISSN号 | 0920-654X |
| 关键词 | P38 alpha Molecular dynamics simulation Binding free energy Chirality Inhibitor |
| DOI | 10.1007/s10822-009-9298-8 |
| 通讯作者 | Ji, mingjuan(jmj@gucas.ac.cn) |
| 英文摘要 | 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazines have been discovered as inhibitors of p38 alpha. experimental assays have proven that the configuration of alpha-me-benzyl connected with amide at c6 is essential for the binding affinity. the s-configured inhibitor (11j) displays 80 times more potency than the r-configured one (11k). here we investigated the mechanism how different configurations influence the binding affinity using molecular dynamics simulations, free energy calculations and free energy decomposition analysis. we found that the van der waals interactions play the most important role in differentiating the activities between 11j and 11k with p38 alpha. the difference of the van der waals interactions is primarily determined by two residues, leu108 and leu167. consequently stabilization of pyrrolo[2,1-f][1,2,4]triazine ring is important for the activities of inhibitors. meanwhile we observed that the different configuration of the alpha-me-benzyl group leads to the difference of binding between 11j and 11k. in conclusion, our work shows that it is feasible to analyze the chirality effect of inhibitors with different configurations by molecular dynamics simulations and free energy calculations, and provides useful information for drug design. |
| WOS关键词 | P38 MAP KINASE ; AMPHIPHYSIN-1 SH3 DOMAIN ; CONTINUUM SOLVENT MODELS ; FORCE-FIELD ; RHEUMATOID-ARTHRITIS ; DIVERSE SET ; INHIBITORS ; BINDING ; ACTIVATION ; AFFINITIES |
| WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics ; Computer Science |
| WOS类目 | Biochemistry & Molecular Biology ; Biophysics ; Computer Science, Interdisciplinary Applications |
| 语种 | 英语 |
| 出版者 | SPRINGER |
| WOS记录号 | WOS:000271734500006 |
| URI标识 | http://www.irgrid.ac.cn/handle/1471x/2402619 |
| 专题 | 中国科学院大学 |
| 通讯作者 | Ji, Mingjuan |
| 作者单位 | Chinese Acad Sci, Coll Chem & Chem Engn, Grad Univ, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Quan,Cui, Wei,Ji, Mingjuan. Studies of chirality effect of 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine on p38 alpha by molecular dynamics simulations and free energy calculations[J]. Journal of computer-aided molecular design,2009,23(10):737-745. |
| APA | Chen, Quan,Cui, Wei,&Ji, Mingjuan.(2009).Studies of chirality effect of 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine on p38 alpha by molecular dynamics simulations and free energy calculations.Journal of computer-aided molecular design,23(10),737-745. |
| MLA | Chen, Quan,et al."Studies of chirality effect of 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine on p38 alpha by molecular dynamics simulations and free energy calculations".Journal of computer-aided molecular design 23.10(2009):737-745. |
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来源：中国科学院大学
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