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

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.

journal_name

Acta Pharmacol Sin

journal_title

Acta pharmacologica Sinica

authors

Cheng JX,Cheng T,Li WH,Liu GX,Zhu WL,Tang Y

doi

10.1038/aps.2017.132

subject

Has Abstract

pub_date

2018-03-01 00:00:00

pages

482-491

issue

3

eissn

1671-4083

issn

1745-7254

pii

aps2017132

journal_volume

39

pub_type

杂志文章

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