Conformations and pharmacophores of cyclic RGD containing peptides which selectively bind integrin alpha(v)beta3.
This paper reports a detailed conformational characterization in solution by 1H-NMR in H2O and DMSO-d6 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 alpha(v)beta3. The peptides containing the RGDDY(Me)R sequence bind potently to integrin alphaIIb3 as well. The conformations found in H2O and in DMSO-d6 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.
Locardi
E
E
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093-0343, USA.
Mullen
D G
DG
Mattern
R H
RH
Goodman
M
M
D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000737:chemistry*
D009842:Oligopeptides; D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; C047981:arginyl-glycyl-aspartic acid