Computational insights into the subtype selectivity and "message-address-efficacy" mechanisms of opioid receptors through JDTic binding and unbinding
文献类型：期刊论文
| 作者 | Cheng, Jian-xin1,2; Cheng, Tao1; Li, Wei-hua1; Liu, Gui-xia1; Zhu, Wei-liang2 ; Tang, Yun1
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| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2018-03 |
| 卷号 | 39期号:3页码:482-491 |
| 关键词 | G-protein-coupled receptors opioid receptors subtype selectivity molecular dynamics "message-address-efficacy" hypothesis JDTic |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2017.132 |
| 文献子类 | Article |
| 英文摘要 | In drug design and discovery, binding affinity and selectivity are two basic properties of a drug candidate. Opioid receptors (ORs) are the main targets of strong analgesics. Like some other class A members of G-protein-coupled receptors (GPCRs), ORs exhibit complex selectivity on their ligands. The diversity of binding activity and selectivity among opioids has deeply attracted researchers for a long time. To investigate the subtype selectivity of mu, delta and kappa. ORs in detail, using the kappa-selective antagonist JDTic as a probe, we performed a series of computational simulations, including molecular dynamics and metadynamics, on JDTic-mu/delta/kappa-OR complexes. From the simulations, we found that the decisive factor of JDTic selectivity on the mu-subtype was the 2.63 position, which affected the efficacy of JDTic through changing the dynamics of the Q(2.60) residue. In addition to the 2.63-position residue, the 7.35 position was the other crucial aspect of JDTic selectivity for the delta-subtype. Based on the results, we suggest a new concept, the "message-address-efficacy" hypothesis, to explain the relationships among the affinity, selectivity and function between ORs and opioids. Thus, all the detailed dynamics of JDTic-bound ORs might be helpful to deeply understand the subtype selectivity and binding mechanisms of other GPCRs. |
| WOS关键词 | PROTEIN-COUPLED RECEPTORS ; GENERAL FORCE-FIELD ; SITE-DIRECTED MUTAGENESIS ; FUNCTIONAL SELECTIVITY ; ANTAGONIST ; KAPPA ; POTENT ; NALTRINDOLE ; DISCOVERY ; LIGANDS |
| 资助项目 | National Key Research and Development Program of China[2016YFA0502304] ; National Natural Science Foundation of China[81673356] ; National Natural Science Foundation of China[U1603122] ; 111 Project[B07023] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:6174722 |
| WOS记录号 | WOS:000426844400015 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279874]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Tang, Yun |
| 作者单位 | 1.East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China; 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Cheng, Jian-xin,Cheng, Tao,Li, Wei-hua,et al. Computational insights into the subtype selectivity and "message-address-efficacy" mechanisms of opioid receptors through JDTic binding and unbinding[J]. ACTA PHARMACOLOGICA SINICA,2018,39(3):482-491. |
| APA | Cheng, Jian-xin,Cheng, Tao,Li, Wei-hua,Liu, Gui-xia,Zhu, Wei-liang,&Tang, Yun.(2018).Computational insights into the subtype selectivity and "message-address-efficacy" mechanisms of opioid receptors through JDTic binding and unbinding.ACTA PHARMACOLOGICA SINICA,39(3),482-491. |
| MLA | Cheng, Jian-xin,et al."Computational insights into the subtype selectivity and "message-address-efficacy" mechanisms of opioid receptors through JDTic binding and unbinding".ACTA PHARMACOLOGICA SINICA 39.3(2018):482-491. |
入库方式： OAI收割
来源：上海药物研究所
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