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

Jian-xin CHENG1,2, Tao CHENG1, Wei-hua LI1, Gui-xia LIU1, Wei-liang ZHU2, Yun TANG1
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
Correspondence to: Yun TANG:,
DOI: 10.1038/aps.2017.132
Received: 3 May 2017
Accepted: 21 June 2017
Advance online: 19 October 2017


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.
Keywords: G-protein-coupled receptors; opioid receptors; subtype selectivity; molecular dynamics; “message-address-efficacy” hypothesis; JDTic

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