Dissecting the innate immune recognition of opioid inactive isomer (+)-naltrexone derived toll-like receptor 4 (TLR4) antagonists

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dc.contributor.authorZhang, X.
dc.contributor.authorCui, F.
dc.contributor.authorChen, H.
dc.contributor.authorZhang, T.
dc.contributor.authorYang, K.
dc.contributor.authorWang, Y.
dc.contributor.authorJiang, Z.
dc.contributor.authorRice, K.C.
dc.contributor.authorWatkins, L.R.
dc.contributor.authorHutchinson, M.R.
dc.contributor.authorLi, Y.
dc.contributor.authorPeng, Y.
dc.contributor.authorWang, X.
dc.date.issued2018
dc.description.abstractThe opioid inactive isomer (+)-naltrexone is one of the rare Toll-like receptor 4 (TLR4) antagonists with good blood-brain barrier (BBB) permeability, which is a lead with promising potential for treating neuropathic pain and drug addiction. (+)-Naltrexone targets the lipopolysaccharides (LPS) binding pocket of myeloid differentiation protein 2 (MD-2) and blocks innate immune TLR4 signaling. However, the details of the molecular interactions of (+)-naltrexone and its derivatives with MD-2 are not fully understood, which hinders the ligand-based drug discovery. Herein, in silico and in vitro assays were performed to elucidate the innate immune recognition of the opioid inactive (+)-isomers. The results showed that the conserved LPS binding pocket of MD-2 accommodated these opioid inactive (+)-isomers. The calculated binding free energies of (+)-naltrexone and its derivatives in complex with MD-2 correlated well with their experimental binding affinities and TLR4 antagonistic activities. Hydrophobic residues in the MD-2 cavity interacted directly with these (+)-naltrexone based TLR4 antagonists and principally participated in ligand binding. Increasing the hydrophobicity of substituted group at N-17 improved its TLR4 antagonistic activity, while charged groups disfavored the binding with MD-2. Molecular dynamics (MD) simulations showed the binding of (+)-naltrexone or its derivatives to MD-2 stabilized the "collapsed" conformation of MD-2, consequently blocking the binding and signaling of TLR4. Thermodynamics and dynamic analysis showed the topology of substituted group at N-17 of (+)-naltrexone affected the binding with MD-2 and TLR4 antagonistic activity. This study provides a molecular insight into the innate immune recognition of opioid inactive (+)-isomers, which would be of great help for the development of next-generation of (+)-opioid based TLR4 antagonists.
dc.description.statementofresponsibilityXiaozheng Zhang, Fengchao Cui, Hongqian Chen, Tianshu Zhang, Kecheng Yang, Yibo Wang ... et al.
dc.identifier.citationJournal of Chemical Information and Modeling, 2018; 58(4):816-825
dc.identifier.doi10.1021/acs.jcim.7b00717
dc.identifier.issn1549-9596
dc.identifier.issn1520-5142
dc.identifier.orcidHutchinson, M.R. [0000-0003-2154-5950]
dc.identifier.urihttp://hdl.handle.net/2440/129613
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.rights© 2018 American Chemical Society
dc.source.urihttps://doi.org/10.1021/acs.jcim.7b00717
dc.subjectNaltrexone
dc.subjectAnalgesics, Opioid
dc.subjectBinding Sites
dc.subjectProtein Conformation
dc.subjectProtein Binding
dc.subjectStructure-Activity Relationship
dc.subjectIsomerism
dc.subjectToll-Like Receptor 4
dc.subjectImmunity, Innate
dc.subjectMolecular Dynamics Simulation
dc.subjectMolecular Docking Simulation
dc.titleDissecting the innate immune recognition of opioid inactive isomer (+)-naltrexone derived toll-like receptor 4 (TLR4) antagonists
dc.typeJournal article
pubs.publication-statusPublished

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