Biological and conformational study of β-substituted prolines in MT-II template

Steric effects leading to human MC5 receptor selectivity

Minying Cai, C. Cai, A. V. Mayorov, C. Xiong, C. M. Cabello, V. A. Soloshonok, J. R. Swift, D. Trivedi, Victor J Hruby

Research output: Contribution to journalArticle

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Abstract

To investigate the molecular basis for the interaction of the χ-constrained conformation of melanotropin peptide with the human melanocortin receptors, a series of β-substituted proline analogs were synthesized and incorporated into the Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]- NH2 (MT-II) template at the His6 and D-Phe7 positions. It was found that the binding affinities generally diminished as the steric bulk of the p-substituents of the 3-phenylproline residues increased. From (25, 3R)-3-phenyl-Pro6 to (2S, 3R)-3-(p-methoxyphenyl)-Pro 6 analogs the binding affinity decreased 23-fold at the human melanocortin-3 receptor (hMC3R), 17-fold at the hMC4R, and eight-fold at the hMC5R, but selectivity for the hMC5R increased. In addition, the substitution of the D-Phe7 residue with a (2R, 3S)-3-phenyl-Pro resulted in greatly reduced binding affinity (103-105) at these melanocortin receptors. Macromodel's Large Scale Low Mode (LLMOD) with OPLS-AA force field simulations revealed that both MT-II and SHU-9119 share a similar backbone conformation and topography with the exception of the orientation of the side chains of D-Phe7/D-Nal (2′)7 in χ space. Introduction of the dihedrally constrained phenylproline analogs into the His6 position (analogs 2-6) caused topographical changes that might be responsible for the lower binding affinities. Our findings indicate that hMC3 and hMC4 receptors are more sensitive to steric effects and conformational constraints than the hMC5 receptor. This is the first example for melanocortin receptor selectivity where the propensity of steric interactions in χ space of β-modified Pro6 analogs of MT-II has been shown to play a critical role for binding as well as bioefficacy of melanotropins at hMC3 and hMC4 receptors, but not at the hMC5 receptor.

Original languageEnglish (US)
Pages (from-to)116-131
Number of pages16
JournalJournal of Peptide Research
Volume63
Issue number2
DOIs
StatePublished - Feb 2004

Fingerprint

Melanocortin Receptors
Proline
Melanocyte-Stimulating Hormones
Conformations
Crystal orientation
Topography
Substitution reactions
Peptides
melanocortin 5 receptor

Keywords

  • α-MSH
  • hMC5R
  • Melanocortin receptors
  • Melanotropin agonists
  • Melanotropin antagonists
  • MT-II
  • Selective ligands
  • Steric constraints

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

Biological and conformational study of β-substituted prolines in MT-II template : Steric effects leading to human MC5 receptor selectivity. / Cai, Minying; Cai, C.; Mayorov, A. V.; Xiong, C.; Cabello, C. M.; Soloshonok, V. A.; Swift, J. R.; Trivedi, D.; Hruby, Victor J.

In: Journal of Peptide Research, Vol. 63, No. 2, 02.2004, p. 116-131.

Research output: Contribution to journalArticle

Cai, Minying ; Cai, C. ; Mayorov, A. V. ; Xiong, C. ; Cabello, C. M. ; Soloshonok, V. A. ; Swift, J. R. ; Trivedi, D. ; Hruby, Victor J. / Biological and conformational study of β-substituted prolines in MT-II template : Steric effects leading to human MC5 receptor selectivity. In: Journal of Peptide Research. 2004 ; Vol. 63, No. 2. pp. 116-131.
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AU - Cai, C.

AU - Mayorov, A. V.

AU - Xiong, C.

AU - Cabello, C. M.

AU - Soloshonok, V. A.

AU - Swift, J. R.

AU - Trivedi, D.

AU - Hruby, Victor J

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N2 - To investigate the molecular basis for the interaction of the χ-constrained conformation of melanotropin peptide with the human melanocortin receptors, a series of β-substituted proline analogs were synthesized and incorporated into the Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]- NH2 (MT-II) template at the His6 and D-Phe7 positions. It was found that the binding affinities generally diminished as the steric bulk of the p-substituents of the 3-phenylproline residues increased. From (25, 3R)-3-phenyl-Pro6 to (2S, 3R)-3-(p-methoxyphenyl)-Pro 6 analogs the binding affinity decreased 23-fold at the human melanocortin-3 receptor (hMC3R), 17-fold at the hMC4R, and eight-fold at the hMC5R, but selectivity for the hMC5R increased. In addition, the substitution of the D-Phe7 residue with a (2R, 3S)-3-phenyl-Pro resulted in greatly reduced binding affinity (103-105) at these melanocortin receptors. Macromodel's Large Scale Low Mode (LLMOD) with OPLS-AA force field simulations revealed that both MT-II and SHU-9119 share a similar backbone conformation and topography with the exception of the orientation of the side chains of D-Phe7/D-Nal (2′)7 in χ space. Introduction of the dihedrally constrained phenylproline analogs into the His6 position (analogs 2-6) caused topographical changes that might be responsible for the lower binding affinities. Our findings indicate that hMC3 and hMC4 receptors are more sensitive to steric effects and conformational constraints than the hMC5 receptor. This is the first example for melanocortin receptor selectivity where the propensity of steric interactions in χ space of β-modified Pro6 analogs of MT-II has been shown to play a critical role for binding as well as bioefficacy of melanotropins at hMC3 and hMC4 receptors, but not at the hMC5 receptor.

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