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Conformations and pharmacophores of cyclic RGD containing peptides which selectively bind integrin α v β 3
Author(s) -
Locardi Elsa,
Mullen Daniel G.,
Mattern RalphHeiko,
Goodman Murray
Publication year - 1999
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/(sici)1099-1387(199911)5:11<491::aid-psc218>3.0.co;2-8
Subject(s) - pharmacophore , chemistry , peptidomimetic , pentapeptide repeat , stereochemistry , cyclic peptide , integrin , combinatorial chemistry , peptide , receptor , biochemistry
This paper reports a detailed conformational characterization in solution by 1 H‐NMR in H 2 O and DMSO‐d 6 and molecular modeling simulations of cyclic peptides containing the RGDDV pharmacophore and the RGDY(Me)R pharmacophore. These two pentapeptide sequences when properly constrained in cyclic peptides are low to sub‐nanomolar inhibitors of integrin α v β 3 . The peptides containing the RGDDY(Me)R sequence bind potently to integrin α IIb β 3 as well. The conformations found in H 2 O and in DMSO‐d 6 solutions are valuable for the design of peptidomimetics of these two pharmacophores. The structure–activity relationships of the RGDDV and RGDY(Me)R pharmacophores within cyclic peptides are discussed. Specifically, the orientation of surface‐accessible chemical features on the ligand, such as hydrophobic, positive and negative ionizable groups, which are considered to be responsible for the desired biological activity, is focused on. Copyright © 1999 European Peptide Society and John Wiley & Sons, Ltd.