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Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

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dc.abstract.en: Interactions of 21 fentanyl derivatives with µ-opioid receptor (µOR) were studied using experimental and theoretical methods. Their binding to µOR was assessed with radioligand competitive binding assay. A uniform set of binding affinity data contains values for two novel and one previously uncharacterized derivative. The data confirms trends known so far and thanks to their uniformity, they facilitate further comparisons. In order to provide structural hypotheses explaining the experimental affinities, the complexes of the studied derivatives with µOR were modeled and subject to molecular dynamics simulations. Five common General Features (GFs) of fentanyls’ binding modes stemmed from these simulations. They include: GF1) the ionic interaction between D147 and the ligands’ piperidine NH+ moiety; GF2) the N-chain orientation towards the µOR interior; GF3) the other pole of ligands is directed towards the receptor outlet; GF4) the aromatic anilide ring penetrates the subpocket formed by TM3, TM4, ECL1 and ECL2; GF5) the 4-axial substituent (if present) is directed towards W318. Except for the ionic interaction with D147, the majority of fentanyl-µOR contacts is hydrophobic. Interestingly, it was possible to find nonlinear relationships between the binding affinity and the volume of the N-chain and/or anilide’s aromatic ring. This kind of relationships is consistent with the apolar character of interactions involved in ligand–receptor binding. The affinity reaches the optimum for medium size while it decreases for both large and small substituents. Additionally, a linear correlation between the volumes and the average dihedral angles of W293 and W133 was revealed by the molecular dynamics study. This seems particularly important, as the W293 residue is involved in the activation processes. Further, the Y326 (OH) and D147 (Cγ) distance found in the simulations also depends on the ligands’ size. In contrast, neither RMSF measures nor D114/Y336 hydrations show significant structure-based correlations. They also do not differentiate studied fentanyl derivatives. Eventually, none of 14 popular scoring functions yielded a significant correlation between the predicted and observed affinity data (R < 0.30, n = 28).
dc.affiliationUniwersytet Warszawski
dc.contributor.authorMisicka-Kęsik, Aleksandra
dc.contributor.authorLipiński, Piotr
dc.contributor.authorJarończyk, Małgorzata
dc.contributor.authorMatalińska, Joanna
dc.contributor.authorSadlej, Joanna
dc.contributor.authorCzarnocki, Zbigniew
dc.contributor.authorKosson, Piotr
dc.contributor.authorRoszkowski, Piotr
dc.contributor.authorDobrowolski, Jan
dc.date.accessioned2024-01-25T00:39:56Z
dc.date.available2024-01-25T00:39:56Z
dc.date.copyright2019-02-19
dc.date.issued2019
dc.description.accesstimeAT_PUBLICATION
dc.description.financeNie dotyczy
dc.description.number4
dc.description.versionFINAL_PUBLISHED
dc.description.volume24
dc.identifier.doi10.3390/MOLECULES24040740
dc.identifier.issn1420-3049
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/107058
dc.identifier.weblinkhttps://www.mdpi.com/1420-3049/24/4/740
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofMolecules
dc.relation.pages740
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.enfentanyl
dc.subject.enopioid receptors
dc.subject.enmolecular dynamics
dc.subject.endesigner drugs
dc.titleFentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis
dc.typeJournalArticle
dspace.entity.typePublication