Molecular Modeling of the 3D Structure of 5-HT1AR: Discovery of Novel 5-HT1AR Agonists via Dynamic Pharmacophore-Based Virtual Screening
文献类型：期刊论文
| 作者 | Xu, Lili2,3; Zhou, Shanglin4; Yu, Kunqian4 ; Gao, Bo1; Jiang, Hualiang4; Zhen, Xuechu1; Fu, Wei2,3
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| 刊名 | JOURNAL OF CHEMICAL INFORMATION AND MODELING
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| 出版日期 | 2013-12 |
| 卷号 | 53期号:12页码:3202-3211 |
| ISSN号 | 1549-9596 |
| DOI | 10.1021/ci400481p |
| 文献子类 | Article |
| 英文摘要 | The serotonin receptor subtype 1A (5-HT1AR) has been implicated in several neurological conditions, and potent 5-HT1AR agonists have therapeutic potential for the treatment of depression, anxiety, schizophrenia, and Parkinson's disease. In the present study, a homology model of 5-HT1AR was built based on the latest released high-resolution crystal structure of the beta(2)AR in its active state (PDB: 3SN6). A dynamic pharmacophore model, which takes the receptor flexibility into account, was constructed, validated, and applied to our dynamic pharmacophore-based virtual screening approach with the aim to identify potential 5-HT1AR agonists. The obtained hits were subjected to 5-HT1AR binding and functional assays, and 10 compounds with medium or high K-i and EC50 values were identified. Among them, FW01 (K-i = 51.9 nM, EC50 = 7 nM) was evaluated as the strongest agonist for 5-HT1AR The active 5-HT1AR model and dynamic. pharmacophore model obtained from this study can be used for future discovery and design of novel 5-HT1AR agonists. Also, by integrating all computational and available experimental data, a stepwise 5-HT1AR signal transduction model induced by agonist FW01 was proposed. |
| WOS关键词 | LIGAND-BINDING ; RECEPTOR AGONIST ; HIV-1 INTEGRASE ; SEROTONIN ; IDENTIFICATION ; RESIDUES ; DOCKING ; PROFILE ; SITE ; SIMULATIONS |
| 资助项目 | National Natural Science Foundation of China[81172919] ; National Natural Science Foundation of China[81130023] ; National Natural Science Foundation of China[30825042] ; State Key Laboratory of Drug Research[00000000] ; National High Technology Research and Development Program of China (863 Program)[2012AA020301] ; State Key Program of Basic Research of China[2009CB918502] ; State Key Program of Basic Research of China[2010CB912601] ; State Key Program of Basic Research of China[2009CB522000] ; State Key Program of Basic Research of China[2011CB5C4403] ; National Drug Innovative Program[2009ZX09301-011] ; Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD)[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry ; Computer Science |
| 语种 | 英语 |
| WOS记录号 | WOS:000329137700011 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277347]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Jiang, Hualiang |
| 作者单位 | 1.Soochow Univ, Dept Pharmacol, Coll Pharmaceut Sci, Suzhou 215123, Peoples R China 2.Fudan Univ, Minist Educ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China; 3.Fudan Univ, Minist Educ, Sch Pharm, Key Lab Smart Drug Delivery, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Xu, Lili,Zhou, Shanglin,Yu, Kunqian,et al. Molecular Modeling of the 3D Structure of 5-HT1AR: Discovery of Novel 5-HT1AR Agonists via Dynamic Pharmacophore-Based Virtual Screening[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2013,53(12):3202-3211. |
| APA | Xu, Lili.,Zhou, Shanglin.,Yu, Kunqian.,Gao, Bo.,Jiang, Hualiang.,...&Fu, Wei.(2013).Molecular Modeling of the 3D Structure of 5-HT1AR: Discovery of Novel 5-HT1AR Agonists via Dynamic Pharmacophore-Based Virtual Screening.JOURNAL OF CHEMICAL INFORMATION AND MODELING,53(12),3202-3211. |
| MLA | Xu, Lili,et al."Molecular Modeling of the 3D Structure of 5-HT1AR: Discovery of Novel 5-HT1AR Agonists via Dynamic Pharmacophore-Based Virtual Screening".JOURNAL OF CHEMICAL INFORMATION AND MODELING 53.12(2013):3202-3211. |
入库方式： OAI收割
来源：上海药物研究所
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