dc.contributor.author
Puls, Kristina
dc.contributor.author
Schmidhammer, Helmut
dc.contributor.author
Wolber, Gerhard
dc.contributor.author
Spetea, Mariana
dc.date.accessioned
2022-05-13T13:31:26Z
dc.date.available
2022-05-13T13:31:26Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/35017
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-34733
dc.description.abstract
Accumulated preclinical and clinical data show that peripheral restricted opioids provide pain relief with reduced side effects. The peripherally acting opioid analgesic HS-731 is a potent dual μ-/δ-opioid receptor (MOR/DOR) full agonist, and a weak, partial agonist at the κ-opioid receptor (KOR). However, its binding mode at the opioid receptors remains elusive. Here, we present a comprehensive in silico evaluation of HS-731 binding at all opioid receptors. We provide insights into dynamic interaction patterns explaining the different binding and activity of HS-731 on the opioid receptors. For this purpose, we conducted docking, performed molecular dynamics (MD) simulations and generated dynamic pharmacophores (dynophores). Our results highlight two residues important for HS-731 recognition at the classical opioid receptors (MOR, DOR and KOR), particular the conserved residue 5.39 (K) and the non-conserved residue 6.58 (MOR: K, DOR: W and KOR: E). Furthermore, we assume a salt bridge between the transmembrane helices (TM) 5 and 6 via K2275.39 and E2976.58 to be responsible for the partial agonism of HS-731 at the KOR. Additionally, we experimentally demonstrated the absence of affinity of HS-731 to the nociceptin/orphanin FQ peptide (NOP) receptor. We consider the morphinan phenol Y1303.33 responsible for this affinity lack. Y1303.33 points deep into the NOP receptor binding pocket preventing HS-731 binding to the orthosteric binding pocket. These findings provide significant structural insights into HS-731 interaction pattern with the opioid receptors that are important for understanding the pharmacology of this peripheral opioid analgesic.
en
dc.format.extent
19 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
opioid receptor
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::540 Chemie::540 Chemie und zugeordnete Wissenschaften
dc.title
Mechanistic Characterization of the Pharmacological Profile of HS-731, a Peripherally Acting Opioid Analgesic, at the µ-, δ-, κ-Opioid and Nociceptin Receptors
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
919
dcterms.bibliographicCitation.doi
10.3390/molecules27030919
dcterms.bibliographicCitation.journaltitle
Molecules
dcterms.bibliographicCitation.number
3
dcterms.bibliographicCitation.originalpublishername
MDPI
dcterms.bibliographicCitation.volume
27
dcterms.bibliographicCitation.url
https://doi.org/10.3390/molecules27030919
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Pharmazie
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access