Computational insights into the subtype selectivity and "message-address-efficacy" mechanisms of opioid receptors through JDTic binding and unbinding.
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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 ?, ? and ? ORs in detail, using the ?-selective antagonist JDTic as a probe, we performed a series of computational simulations, including molecular dynamics and metadynamics, on JDTic-?/?/?-OR complexes. From the simulations, we found that the decisive factor of JDTic selectivity on the ?-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 ?-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.
SUBMITTER: Cheng JX
PROVIDER: S-EPMC5843831 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
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