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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
Year:
1994
Source of publication :
Journal of Medicinal Chemistry
Authors :
Zeltser, Irina
;
.
Volume :
37
Co-Authors:
Grdadolnik, S.G., Institut fûr Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany, National Institute of Chemistry, Hajdrihova 19, SLO-61000 Ljubljana, Slovenia
Mierke, D.F., Institut fûr Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany, Department of Chemistry, Clark University, Worcester, MA 06160, United States
Byk, G., Department of Organic Chemistry, Hebrew University of Jerusalem, I-91904 Jerusalem, Israel
Zeltser, I., Department of Organic Chemistry, Hebrew University of Jerusalem, I-91904 Jerusalem, Israel
Gilon, C., Department of Organic Chemistry, Hebrew University of Jerusalem, I-91904 Jerusalem, Israel
Kessler, H., Institut fûr Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany
Facilitators :
From page:
2145
To page:
2152
(
Total pages:
8
)
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. © 1994 American Chemical Society.
Note:
Related Files :
computer simulation
drug conformation
neurokinin 1 receptor
nuclear overhauser effect
Phenylalanine
water
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More details
DOI :
Article number:
Affiliations:
Database:
Scopus
Publication Type:
article
;
.
Language:
English
Editors' remarks:
ID:
21688
Last updated date:
02/03/2022 17:27
Creation date:
16/04/2018 23:46
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Scientific Publication
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
37
Grdadolnik, S.G., Institut fûr Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany, National Institute of Chemistry, Hajdrihova 19, SLO-61000 Ljubljana, Slovenia
Mierke, D.F., Institut fûr Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany, Department of Chemistry, Clark University, Worcester, MA 06160, United States
Byk, G., Department of Organic Chemistry, Hebrew University of Jerusalem, I-91904 Jerusalem, Israel
Zeltser, I., Department of Organic Chemistry, Hebrew University of Jerusalem, I-91904 Jerusalem, Israel
Gilon, C., Department of Organic Chemistry, Hebrew University of Jerusalem, I-91904 Jerusalem, Israel
Kessler, H., Institut fûr Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany
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
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. © 1994 American Chemical Society.
Scientific Publication
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