文献类型：期刊文献

中文题名：Computational insights into the subtype selectivity and ＂message-address-efficacy＂ mechanisms of opioid receptors through JDTic binding and unbinding

英文题名：Computational insights into the subtype selectivity and ＂message-address-efficacy＂ mechanisms of opioid receptors through JDTic binding and unbinding

作者：Jian-xin CHENG[1,2];Tao CHENG[1];Wei-hua LI[1];Gui-xia LIU[2];Wei-liang ZHU[2];Yun TANG[1]

机构：[1]Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;[2]Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

年份：2018

卷号：39

期号：3

起止页码：482

中文期刊名：Acta Pharmacologica Sinica

外文期刊名：中国药理学报（英文版）

收录：CSTPCD;;Scopus;CSCD:【CSCD2017_2018】；PubMed;

基金：All the simulations were performed using the high-performance cluster kindly provided by Prof Bang-ce YE of the State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology. This work was supported by the National Key Research and Development Program of China （Grant 2016YFA0502304）, the National Natural Science Foundation of China （Grants 81673356 and U1603122） and the 111 Project （Grant B07023）.

语种：英文

中文关键词：G-protein-coupled receptors; opioid receptors; subtype selectivity; molecular dynamics; ＂message-address-efficacy＂hypothesis; JDTic

外文关键词：G-protein-coupled receptors; opioid receptors; subtype selectivity; molecular dynamics; ＂message-address-efficacy＂hypothesis; JDTic

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 p, 5 and K ORs in detail, using the K-selective antagonist JDTic as a probe, we performed a series of computational simulations, including molecular dynamics and metadynamics, on JDTic-p/5/K-OR complexes. From the simulations, we found that the decisive factor of JDTic selectivity on the p-subtype was the 2.63 position, which affected the efficacy of JDTic through changing the dynamics of the Q2.60 residue. In addition to the 2.63-position residue, the 7.35 position was the other crucial aspect of JDTic selectivity for the 5-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.
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 p, 5 and K ORs in detail, using the K-selective antagonist JDTic as a probe, we performed a series of computational simulations, including molecular dynamics and metadynamics, on JDTic-p/5/K-OR complexes. From the simulations, we found that the decisive factor of JDTic selectivity on the p-subtype was the 2.63 position, which affected the efficacy of JDTic through changing the dynamics of the Q2.60 residue. In addition to the 2.63-position residue, the 7.35 position was the other crucial aspect of JDTic selectivity for the 5-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.