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

Abstract

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.

Identification and characterization of plant-derived alkaloids, corydine and corydaline, as novel mu opioid receptor agonists

“…It is commonly recognized that hits identified in a virtual screening campaign often display weaker activity than the compounds the models were based on 26 , 53 . Our docking study to the MOR revealed that both compounds share several essential receptor-ligand interactions, including the salt bridge with Asp147 and hydrogen bond formation with Tyr148 (water-mediated in the case of corydaline ( 2 ), analogous to BU72), as two residues recognized as key interaction sites for ligand (small molecules and peptides) binding to the MOR 24 – 34 , 54 . However, there are also receptor-ligand interaction pattern dissimilarities.…”

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

“…Similar binding poses were also proposed based on molecular modelling results for the opioid fragment of other opioid/antitachykinin hybrids [ 17 ] or some Tyr- d -Ala-Phe-Phe (TAPP) derivatives [ 66 ]. Aromatic rings of BU72 (experiment [ 67 ]), fentanyl (modelling [ 68 ]) cyclic opioid derivatives (modelling [ 69 ]), or linear peptide opioids (modelling [ 70 ]) were found to be located similarly as the Phe 4 ring in MOR-1 pose. For the -NH-NH-Z- d -Trp fragment, a few quite distinct binding poses are found at MOR.…”

Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review

“…The activity of DMT-DALDA (H-Dmt-D-Arg-Phe-Lys-NH2; Dmt = 2′,6′-dimethyltyrosine), a selective mu opioid agonist, was equivalent to morphine in producing MC degranulation, although it was greater than a 1000-fold more potent in producing analgesia, suggesting a possible lower risk in producing a spinal mass at equivalent analgesic concentrations [157]. Moreover, the Dmt (2′,6′-dimethyl-L-Tyr) moiety of DMT-DALDA was found to represent the driving force for the high potency and agonist activity at the mu opioid receptor (MOR), and the key amino acid residues Y148 3.33 and Y326 7.42 were responsible for DMT-DALDA binding to MOR [158]. On the other hand, opioids can induce IgE-mediated MC degranulation.…”