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Article

Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor

1
Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
2
Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany
3
Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
*
Authors to whom correspondence should be addressed.
Contributed equally to this work.
Academic Editor: Derek J. McPhee
Molecules 2020, 25(9), 2087; https://doi.org/10.3390/molecules25092087
Received: 8 April 2020 / Revised: 25 April 2020 / Accepted: 27 April 2020 / Published: 29 April 2020
The mu opioid receptor (MOR) is the primary target for analgesia of endogenous opioid peptides, alkaloids, synthetic small molecules with diverse scaffolds, and peptidomimetics. Peptide-based opioids are viewed as potential analgesics with reduced side effects and have received constant scientific interest over the years. This study focuses on three potent peptide and peptidomimetic MOR agonists, DALDA, [Dmt1]DALDA, and KGOP01, and the prototypical peptide MOR agonist DAMGO. We present the first molecular modeling study and structure–activity relationships aided by in vitro assays and molecular docking of the opioid peptide analogues, in order to gain insight into their mode of binding to the MOR. In vitro binding and functional assays revealed the same rank order with KGOP01 > [Dmt1]DALDA > DAMGO > DALDA for both binding and MOR activation. Using molecular docking at the MOR and three-dimensional interaction pattern analysis, we have rationalized the experimental outcomes and highlighted key amino acid residues responsible for agonist binding to the MOR. The Dmt (2′,6′-dimethyl-L-Tyr) moiety of [Dmt1]DALDA and KGOP01 was found to represent the driving force for their high potency and agonist activity at the MOR. These findings contribute to a deeper understanding of MOR function and flexible peptide ligand–MOR interactions, that are of significant relevance for the future design of opioid peptide-based analgesics. View Full-Text
Keywords: mu opioid receptor; opioid peptides and peptidomimetics; DAMGO; DALDA; [Dmt1]DALDA; KGOP01; binding; molecular docking; structure-activity relationships mu opioid receptor; opioid peptides and peptidomimetics; DAMGO; DALDA; [Dmt1]DALDA; KGOP01; binding; molecular docking; structure-activity relationships
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MDPI and ACS Style

Dumitrascuta, M.; Bermudez, M.; Ballet, S.; Wolber, G.; Spetea, M. Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor. Molecules 2020, 25, 2087. https://doi.org/10.3390/molecules25092087

AMA Style

Dumitrascuta M, Bermudez M, Ballet S, Wolber G, Spetea M. Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor. Molecules. 2020; 25(9):2087. https://doi.org/10.3390/molecules25092087

Chicago/Turabian Style

Dumitrascuta, Maria, Marcel Bermudez, Steven Ballet, Gerhard Wolber, and Mariana Spetea. 2020. "Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor" Molecules 25, no. 9: 2087. https://doi.org/10.3390/molecules25092087

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