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题名: In silico research to assist the investigation of carboxamide derivatives as potent TRPV1 antagonists
作者: Wang, Jinghui1;  Li, Yan1;  Yang, Yinfeng1;  Du, Jian1;  Zhang, Shuwei1;  Yang, Ling2
刊名: MOLECULAR BIOSYSTEMS
发表日期: 2015
DOI: 10.1039/c5mb00356c
卷: 11, 期:11, 页:2885-2899
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Biochemistry & Molecular Biology
研究领域[WOS]: Biochemistry & Molecular Biology
英文摘要: The transient receptor potential vanilloid type 1 (TRPV1), a non-selective cation channel, is known for its essential role in the pathogenesis of various pain conditions such as nerve damage induced hyperalgesia, diabetic neuropathy and cancer pain. Therefore, TRPV1 is considered as a promising target for the development of new anti-inflammatory and analgesic drugs. In the present study, a theoretical study on the functionalities of the molecular interactions between 236 active ligands and TRPV1 was carried out, using three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular docking and molecular dynamics (MD) simulation approaches. The ligand-based CoMSIA model (obtained by use of a random division method for splitting the training and test sets) exhibits optimum predictivity (Q(2) = 0.522, R-ncv(2) = 0.935, R-pred(2) = 0.839). The results show that the models are useful tools for the prediction of the test sets as well as newly designed structures against TRPV1 activity. In addition, to verify the rationality of the random division method for splitting the dataset, we also used a self-organizing map (SOM) division approach for establishing the QSAR models. Interestingly, the obtained optimal CoMSIA model based on the SOM division exhibits almost the same proper statistical results (Q(2) = 0.521, R-ncv(2) = 0.929, R-pred(2) = 0.829) as the random division-derived model, proving the reasonability of both division methods for building the models. The contour plots of molecular fields along with docking and MD simulation have identified several key structural requirements responsible for the activity. The present work provides extremely useful guidelines for future structural modifications of this class of compounds towards the development of superior TRPV1 antagonists. The new computational insights presented in this study are expected to be valuable for the guideline and development of new potent TRPV1 antagonists.
关键词[WOS]: VANILLOID RECEPTOR TRPV1 ;  MOLECULAR-DYNAMICS SIMULATIONS ;  CAPSAICIN RECEPTOR ;  A-425619 1-ISOQUINOLIN-5-YL-3-(4-TRIFLUOROMETHYL-BENZYL)-UREA ;  CHANNEL ACTIVATION ;  RATIONAL SELECTION ;  DRUG DISCOVERY ;  TEST SETS ;  PAIN ;  INHIBITORS
语种: 英语
WOS记录号: WOS:000362950000006
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/146603
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Dalian Univ Technol, Key Lab Ind Ecol & Environm Engn MOE, Fac Chem Environm & Biol Sci & Technol, Dalian 116024, Liaoning, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Grad Sch, Lab Pharmaceut Resource Discovery, Dalian 116023, Liaoning, Peoples R China

Recommended Citation:
Wang, Jinghui,Li, Yan,Yang, Yinfeng,et al. In silico research to assist the investigation of carboxamide derivatives as potent TRPV1 antagonists[J]. MOLECULAR BIOSYSTEMS,2015,11(11):2885-2899.
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