Correlation of molecular shape with GPIIb-IIIa receptor antagonist activity in RGD peptides.

Arg-Gly-Asp-Ser (RGDS) 1, Arg-Val-Asp-Ser (RVDS) 2, Arg-dVal-Asp-Ser (R[d]VDS) 3, and a cyclic RGD peptide, cyclo S,R [H-Pen-Arg-Gly-Asp-Pen-Gly-OH] 4, were tested for their ability to antagonize GPIIb-IIIa function. The activities were found to fall in the order 4 >> 1 >> 3 > 2. Simulated annealing and molecular dynamics studies were carried out to estimate the most populated conformations of each molecule. The acyclic molecules 1-3 were found to populate a much wider range of conformations than the cyclic molecule 4. The backbones of all four molecules were found to approximate beta-turn structures in the most populated conformations. In 4 the beta-turn intramolecular hydrogen bond between C = O of the i residue (Arg) and NH of the i + 3 residue (Ser) did not appear to be present. The distance between the beta-carbons of the critical Arg and Asp groups was found to be shorter in 4 (average 7.98 A) than in the less active acyclic molecules (averages of 8.65-9.33 A).