A Blocking Group Scan Using a Spherical Organometallic Complex Identifies an Unprecedented Binding Mode with Potent Activity In Vitro and In Vivo for the Opioid Peptide Dermorphin

Abstract

Herein, the selective enforcement of one particular receptor-ligand interaction between specific domains of the μ-selective opioid peptide dermorphin and the μ opioid receptor is presented. For this, a blocking group scan is described which exploits the steric demand of a bis(quinolinylmethyl)amine rhenium(I) tricarbonyl complex conjugated to a number of different, strategically chosen positions of dermorphin. The prepared peptide conjugates lead to the discovery of two different binding modes: An expected N-terminal binding mode corresponds to the established view of opioid peptide binding, whereas an unexpected C-terminal binding mode is newly discovered. Surprisingly, both binding modes provide high affinity and agonistic activity at the μ opioid receptor in vitro. Furthermore, the unprecedented C-terminal binding mode shows potent dose-dependent antinociception in vivo. Finally, in silico docking studies support receptor activation by both dermorphin binding modes and suggest a biological relevance for dermorphin itself. Relevant ligand-protein interactions are similar for both binding modes, which is in line with previous protein mutation studies.

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

“…The available crystal structures of the MOR together with efficient computational methods (i.e., molecular docking and molecular dynamics simulations) provide essential insights into binding modes of ligands to the receptor, with the gained knowledge being successfully translated into the discovery of novel bioactive molecules [ 22 , 26 , 27 ]. Most of molecular modeling reports on the active and inactive structures of the MOR targeted small molecules as ligands, with only few studies employing peptides, mostly DAMGO, as the prototypical MOR selective synthetic analogue of the natural peptides enkephalin [ 25 , 28 , 29 ], endomorphin-2, and dermorphin, as endogenous opioid ligands for the MOR [ 30 , 31 ].…”