doi:10.1016/j.bmc.2007.02.050 
Copyright © 2007 Elsevier Ltd All rights reserved.
Conformational analysis of endomorphin-2 analogs with phenylalanine mimics by NMR and molecular modeling
Xuan Shaoa, Yanfeng Gaoa, Chuanjun Zhub, Xuehui Liub, Jinlong Yaoa, Yuxin Cuib, 
, 
and Rui Wanga, c, ,
aState Key Laboratory of Applied Organic Chemistry, Institute of Biochemistry and Molecular Biology, School of Life Science, Lanzhou University, Lanzhou 730000, People’s Republic of China
bState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Medical and Health Analysis Center, Peking University, Beijing 100083, People’s Republic of China
cState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Science, Lanzhou 730000, People’s Republic of China
Received 20 December 2006;
revised 22 February 2007;
accepted 23 February 2007.
Available online 3 March 2007.
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Abstract
We investigated a series of conformations of endomorphin-2 (EM-2) analogs substituted by phenylglycine (Phg) and homophenylalanine (Hfe) in the position 3 or 4 by two-dimensional 1H NMR spectroscopy and molecular modeling. Evaluating the aromatic interactions and the dihedral angles in these phenylalanine mimics, we have observed that the conformations in trans isomer have varied from extended to folded as bioactivity decreases. It is suggested that the flexibility of aromatic side chain affects the backbone of EM-2 to adopt folded structures, which may block the ligands in binding to μ-opioid receptor.
Graphical abstract
The conformations of EM-2 analogs varied from extended to folded structure as bioactivity decreases.
Keywords: Endomorphin-2; Conformation; NMR; Molecular modeling
Figure 1. Schematic diagram of EM-2 and its analogs discussed in the present study.
Figure 2. 1H NMR of cis/trans population observed for the amide and aromatic protons (a) [Phg]4EM-2 and (b) [Hfe]3EM-2 in DMSO-d6 at 298 K.
Figure 3. Part of the 500 MHz ROESY spectrums of [Phg]4EM-2 and [Hfe]3EM-2 in DMSO-d6 at 298 K, showing the assignments of trans- (bold) and cis- (italic) correlation cross peaks with adjacent amino acids.
Figure 4. Ensemble of the 10 most convergent and least violated structures of the family (a) cis-[Phg]4EM-2, (b) trans-[Phg]4EM-2, (c) cis-[Hfe]3EM-2, (d) trans-[Hfe]3EM-2, as determined by DG calculations and molecular dynamics with NOE distance restraints. The mean backbone RMSD of conformational clusters is labeled.
Figure 5. Comparison of the plane angles C2α–C3α–C4α in EM-2 (shown in line) and its analogs (shown in stick) sorted by bioactivity decreases. (a) trans-[Phg]4EM-2, (b) trans-[Hfe]3EM-2, (c) trans-[Hfe]4EM-2, (d) trans-[DPhg]4EM-2, (e) trans-[Phg]3EM-2, (f) trans-[DPhg]3EM-2. The backbone trends have been shown in thick stick and the degrees of angles in EM-2 and its analogs have been labeled, respectively.
Table 1.
The cis/trans ratiosa of EM-2 and its analogs in DMSO-d6 at 298 K
a Determined by integration of
1H NMR.
Table 2.
1H chemical shifts (in ppm) of analogs 5 ([Phg]4EM-2) and 2 ([Hfe]3EM-2) in DMSO-d6 at 298 K
Table 3.
Observed NOE cross peaks and intensities of analogs 5 and 2 in DMSO-d6
a NOE cross peaks of protons in the same carbon are omitted.
b NOE intensities are classified as weak (1.6–5.0 Å), medium (1.6–3.6 Å), and strong (1.6–2.9 Å).
Table 4.
The relationship of aromatic side chains packing in residues of EM-2 and its analogs
Table 5.
Average distance (Å) between the centroids of aromatic rings in EM-2 and its analog clusters of 100 conformations
a Tyr
1 to Phe
3, Hfe
3 or Phg(DPhg)
3.
b Tyr
1 to Phe
4, Hfe
4 or Phg(DPhg)
4.
c Phe
3, Hfe
3 or Phg(DPhg)
3 and Phe
4, Hfe
4 or Phg(DPhg)
4.
d The percentage of distance within 5.5 Å is given in bracket.
Table 6.
Energy (kcal) of cis and trans isomers, and dihedral angles (°) of backbone (
, ψ) and side chain (χ1, χ2) for the trans isomer in analogs of EM-2 with the lowest energy calculated conformation sorted order as bioactivity decreases
Abstract
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