TY - JOUR AU - CHENG Jian-xin AU - CHENG Tao AU - LI Wei-hua AU - LIU Gui-xia AU - ZHU Wei-liang AU - TANG Yun PY - 2018 TI - Computational insights into the subtype selectivity and “message-address-efficacy” mechanisms of opioid receptors through JDTic binding and unbinding JF - Acta Pharmacologica Sinica; Vol 39, No 3 (March 2018): Acta Pharmacologica Sinica Y2 - 2018 KW - N2 - 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 Q 2.60 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. UR - http://www.chinaphar.com/article/view/9749