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Issue 17, 2016
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Computational insights into different inhibition modes of the κ-opioid receptor with antagonists LY2456302 and JDTic

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Abstract

In drug design and discovery, ligand binding kinetics combines pharmacokinetics and pharmacodynamics and more and more attention is paid to it. The κ-opioid G-protein coupled receptor (κ-OR) has been determined to be a promising drug target for the treatment of depression- and anxiety-related diseases. Among the κ-OR selective antagonists, JDTic is a failed antidepressant with a short drug-target residence time (RT), whereas LY2456302 exhibits better effects with a longer RT than JDTic. To investigate the inhibition mechanism of the κ-OR induced by the two ligands, unbiased molecular dynamics and well-tempered metadynamics simulations were performed on JDTic–κ-OR and LY2456302–κ-OR complexes. Through detailed analyses of the simulations, a strong but single interaction mode was found to be responsible for the adverse effects and short RT of JDTic, which could be considered as an alert for other chemotypes, whereas LY2456302 was more advanced, mainly due to its multiple metastable states. Based on Eyring’s equation, the relative RT of LY2456302/JDTic, determined from the activation free energy of dissociation ΔGoff, was efficiently calculated and was in good agreement with experimental data. Thus, these simulations might be helpful for the further design of antidepressants targeting κ-OR with reasonable RT.

Graphical abstract: Computational insights into different inhibition modes of the κ-opioid receptor with antagonists LY2456302 and JDTic

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Publication details

The article was received on 24 Nov 2015, accepted on 19 Jan 2016 and first published on 22 Jan 2016


Article type: Paper
DOI: 10.1039/C5RA24911B
Citation: RSC Adv., 2016,6, 13626-13635
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    Computational insights into different inhibition modes of the κ-opioid receptor with antagonists LY2456302 and JDTic

    J. Cheng, W. Li, G. Liu, W. Zhu and Y. Tang, RSC Adv., 2016, 6, 13626
    DOI: 10.1039/C5RA24911B

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