PMID: 7518522Jul 8, 1994Paper

Comparison of the conformation of active and nonactive backbone cyclic analogs of substance P as a tool to elucidate features of the bioactive conformation: NMR and molecular dynamics in DMSO and water

Journal of Medicinal Chemistry
S G GrdadolnikH Kessler

Abstract

The conformations of two backbone-cyclized substance P analogs as derived from 1H NMR and molecular dynamics simulations carried out in DMSO and water are described. The method of floating chiralities is used in the simulations to facilitate the diastereotopic assignment of methylene protons. One of the analogs, cyclo-[-(CH2)3-NH-CO-(CH2)4-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2, is a highly active, selective agonist for the NK-receptor, while the other, cyclo[-(CH2)2-NH-CO-(CH2)2-Gly-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2, is inactive. Both analogs contain cyclic ring systems of the same size, varying in only the number of amide linkages. From the conformational analysis, the lack of activity can be attributed to the introduction of too much constraint into the ring system. This has an effect on the topological array of the important residues Arg-Phe-Phe. The results presented here are compared with biologically active analogs previously examined. The differences between conformations of active and inactive compounds are used to develop insight into the conformational requirements for biological activity.

Citations

Mar 16, 2000·Journal of Peptide Science : an Official Publication of the European Peptide Society·X F QiV S Ananthanarayanan
Jan 5, 2002·Biopolymers·G R Marshall
Jul 1, 1996·Journal of Peptide Science : an Official Publication of the European Peptide Society·G BitanC Gilon
Jun 10, 2011·Journal of Medicinal Chemistry·Yftah Tal-GanChaim Gilon
Mar 3, 1999·Journal of Biomolecular Structure & Dynamics·E CoutinhoS Srivastava
Mar 24, 2011·Future Medicinal Chemistry·Hadar Benyamini, Assaf Friedler
Oct 19, 2001·The Journal of Peptide Research : Official Journal of the American Peptide Society·I ZeltserC Gilon
Sep 5, 2002·Biopolymers·M Altstein
Dec 1, 1994·Bioscience Reports·Z W Yu, P J Quinn
Mar 3, 2010·Journal of Peptide Science : an Official Publication of the European Peptide Society·Mattan HurevichChaim Gilon
Apr 21, 2011·ChemMedChem·Laura De LucaAlba Chimirri
May 1, 1997·The Journal of Peptide Research : Official Journal of the American Peptide Society·G BitanC Gilon
Sep 13, 2000·Journal of Peptide Science : an Official Publication of the European Peptide Society

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