Conformations and pharmacophores of cyclic RGD containing peptides which selectively bind integrin alpha(v)beta(3)

This paper reports a detailed conformational characterization in solution b y H-1-MMR in H2O and DMSO-d(6) and molecular modeling simulations of cyclic peptides containing the RGDDV pharmacophore and the RGDY(Me)R pharmacophor e. These two pentapeptide sequences when properly constrained in cyclic pep tides are low to sub-nanomolar inhibitors of integrin alpha(v)beta(3). The peptides containing the RGDDY(Me)R sequence bind potently to integrin alpha (IIb)beta(3) as well. The conformations found in H2O and in DMSO-d(6) solut ions are valuable for the design of peptidomimetics of these two pharmacoph ores. The structure-activity relationships of the RGDDV and RGDY(Me)R pharm acophores within cyclic peptides are discussed. Specifically, the orientati on of surface-accessible chemical features on the ligand, such as hydrophob ic, positive and negative ionizable groups, which are considered to be resp onsible for the desired biological activity, is focused on. Copyright (C) 1 999 European Peptide Society and John Wiley & Sons, Ltd.