Ferrocene derivatives of desmuramyl peptide: Synthesis, conformational properties, and interactions with NOD2 receptor

Abstract

Desmuramyl peptide (DMP, l-alanyl-d-isoglutamine) activates the nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) receptor and stimulates the immune response. Herein, we report the design, synthesis, and structural evaluation of the first ferrocene-containing DMPs. The incorporation of the turn-inducing ferrocene scaffolds into peptides often leads to improved conformational stability and biological activity of the resulting peptidomimetics. We have prepared ester-linked (3a/3b) and amide-linked (4a/4b) DMP derivatives containing methylene spacers of different lengths. Experimental structural characterization indicated the presence of an intramolecular hydrogen bond (IHB) forming a ten-membered ring (β-turn) as a folding motif in DMP, and that the type of linker and the length of the alkyl spacer have no significant effect on the IHB patterning. In all derivatives, the α-amide group of isoGln acts as a hydrogen bond donor in β-turns. Docking studies were also performed, which allowed us to investigate the intricate atomic-level interactions between ferrocene derivatives and the target NOD2 receptor. The docking study indicated that derivatives with shorter alkyl spacers are better accommodated in the NOD2 binding site and form stronger interactions with amino acid residues within the binding pocket that are important for MDP binding. The α-amide group of isoGln contributes most to good positioning and hydrogen bond formation within the NOD2 binding pocket.