Dataset Information

Synthesis of Leu-Enkephalin Peptidomimetics Containing Trifluoromethylalkenes as Amide Isopolar Mimics.

ABSTRACT: Fluorinated peptidomimetics are valuable substrates for exploring peptide backbone conformations and for perturbing physicochemical properties of probe compounds. However, in some cases synthetic limitations restrict installation of the fluorinated peptidomimetics into the desired probe compounds. For instance, trifluoromethylalkenes have served as amide isopolar mimics, but are rarely utilized, because many standard peptide-coupling conditions promote the isomerization of the alkene to thermodynamically favored positions. To address this challenge, we report the conversion of a naturally occurring amino acid to a Tyr1-?/[CF3C=CH]-Gly2 dipeptide mimetic, and notably, successful peptide coupling reactions that avoid alkene isomerization. Using this strategy, we generated trifluoromethylalkene-containing Leu-enkephalin peptidomimetics in high purity and good yield. This sequence suggests that the trifluoromethylalkene peptidomimetics can be incorporated into other target molecules with appropriate optimization.

SUBMITTER: Eeda V

PROVIDER: S-EPMC6499489 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Synthesis of Leu-Enkephalin Peptidomimetics Containing Trifluoromethylalkenes as Amide Isopolar Mimics.

Eeda Venkateswararao V Selvaraju Manikandan M Altman Ryan A RA

Journal of fluorine chemistry 20181211

Fluorinated peptidomimetics are valuable substrates for exploring peptide backbone conformations and for perturbing physicochemical properties of probe compounds. However, in some cases synthetic limitations restrict installation of the fluorinated peptidomimetics into the desired probe compounds. For instance, trifluoromethylalkenes have served as amide isopolar mimics, but are rarely utilized, because many standard peptide-coupling conditions promote the isomerization of the alkene to thermody ...[more]

PMID: 31061541

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Project description:The conformational preferences of Leu-enkephalin (Leu-Enk) were explored by the conformational search and density functional theory (DFT) calculations. By a combination of low-energy conformers of each residue, the initial structures of the neutral Leu-Enk were generated and optimized using the ECEPP3 force field in the gas phase. These structures were reoptimized at the HF/3-21G(d) and M06-2X levels of theory with 6-31G(d) and 6-31+G(d) basis functions. We finally located the 139 structures with the relative energy <10 kcal mol-1 in the gas phase, from which the structures of the corresponding zwitterionic Leu-Enk were generated and reoptimized at the M06-2X/6-31+G(d) level of theory using the implicit solvation model based on density (SMD) in water. The conformational preferences of Leu-Enk were analyzed using Gibbs free energies corrected by single-point energies calculated at the double-hybrid DSD-PBEP86-D3BJ/def2-TZVP level of theory in the gas phase and in water. The neutral Leu-Enk dominantly adopted a folded structure in the gas phase stabilized by three H-bonds with a βII'-bend-like motif at the Gly3-Phe4 sequence and a close contact between the side chains of Phe4 and Leu5. The zwitterionic Leu-Enk exhibited a folded structure in water stabilized by three H-bonds with double β-bends such as a βII' bend at the Gly2-Gly3 sequence and a βI bend at the Gly3-Phe4 sequence. The calculated ensemble-averaged distance between CGly2 α and CLeu5 α of the zwitterionic Leu-Enk in water is consistent with the value estimated from the simulated annealing using the distance constraints derived from nuclear Overhauser effect spectroscopy (NOESY) spectra in water. Interestingly, the preferred conformations of the neutral and zwitterionic Leu-Enk are new folded structures not predicted by earlier computational studies. According to the refined model of the zwitterionic Leu-Enk bound to δ-opioid receptor (δOR), there were favorable interactions of the terminal charged groups of Leu-Enk with the side chains of charged residues of δOR as well as a favorable CAryl···H interaction of the Phe4 residue of Leu-Enk with Trp284 of δOR. Hence, these favorable interactions would induce the folded structure of the zwitterionic Leu-Enk with double β-bends isolated in water into the "bioactive conformation" like an extended structure when binding to δOR.

Dataset Information

Synthesis of Leu-Enkephalin Peptidomimetics Containing Trifluoromethylalkenes as Amide Isopolar Mimics.

Publications

Synthesis of Leu-Enkephalin Peptidomimetics Containing Trifluoromethylalkenes as Amide Isopolar Mimics.

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