title: Correlation of molecular shape with GPIIb-IIIa receptor antagonist activity in RGD peptides.
abstract: 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).
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
authors.forename: J S
authors.initials: JS
authors.lastname: Tung
authors.forename: J A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: W F
authors.initials: WF
authors.lastname: Heath
authors.forename: B G
authors.initials: BG
authors.lastname: Utterback
authors.forename: D K
authors.initials: DK
authors.lastname: Herron
mesh_terms: D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011485:Protein Binding; D011487:Protein Conformation; D038981:Receptors, Collagen; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D016023:Integrins; D009842:Oligopeptides; D038981:Receptors, Collagen; D011971:Receptors, Immunologic; C047981:arginyl-glycyl-aspartic acid