@article{APS9749,
author = {Jian-xin CHENG and Tao CHENG and Wei-hua LI and Gui-xia LIU and Wei-liang ZHU and Yun TANG},
title = {Computational insights into the subtype selectivity and “message-address-efficacy” mechanisms of opioid receptors through JDTic binding and unbinding},
journal = {Acta Pharmacologica Sinica},
volume = {39},
number = {3},
year = {2018},
keywords = {},
abstract = {Abstract
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 μ, δ and κ ORs in detail, using the κ-selective antagonist JDTic as a probe, we performed a series of computational simulations, including molecular dynamics and metadynamics, on JDTic-μ/δ/κ-OR complexes. From the simulations, we found that the decisive factor of JDTic selectivity on the μ-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 δ-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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/9749}
}