The relative orientation of the Arg and Asp side chains defined by a pseudodihedral angle as a key criterion for evaluating the structure-activity relationship of RGD peptides.

Abstract

The ability of an integrin to distinguish between the RGD-containing extracellular matrix proteins is thought to be due partially to the variety of RGD conformations. Three criteria have been proposed for the evaluation of the structure-activity relationship of RGD-containing peptides. These include: (i) the distance between the charged centres, (ii) the distance between the Arg Cbeta and Asp Cbeta atoms, and (iii) the pseudo-dihedral angle defining the Arg and Asp side-chain orientation formed by the Arg Czeta, Arg Calpha, Asp Calpha and Asp Cgamma atoms. A comparative conformation-activity study was performed between linear RGD peptides and strongly constrained cyclic (S,S) -CDC- bearing compounds, which cover a wide range of inhibition potency of platelet aggregation. It is concluded that the fulfilment of the -45 degrees < or = pseudo-dihedral angle < or = +45 degrees criterion is a prerequisite for an RGD compound to exhibit inhibitory activity. Once this criterion is accomplished, the longer the distance between the charged centres and/or between the Arg and Asp Cbeta atoms, the higher is the biological activity. In addition, the stronger the ionic interaction between Arg and Asp charged side chains, the lower the anti-aggregatory activity.