A structure-based design of tetrapeptides containing the sequence space D-Phe/X-(P3)-L-Pro(P2)-D-Arg (P1)-P1'-CONH2 was employed to discover potential inhibitors for thrombin (X= analogs of Phe, such as constrained analogs (L)/(D)-Tic [1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid]). The advanced MM3 force-field was used to minimize individual tetrapeptides. The backbone dihedral angles phi and psi were predicted to favor in most cases beta turns and beta hairpin conformation, very similar with the original peptide inhibitor from which they were designed-PPACK. Circular dichroism investigations shows that the D-Arg- in i+3 position followed by D-amino acids (polar and neutral like D-Thr, D-Gln, D-Ser and D-Ala) or L-Pro in i+4 position favors beta turn and beta hairpin structures in solution at low and neutral pH. SAR (structure-activity relationship) suggests that tetrapeptides which adopt beta turn or beta hairpin conformation in solution are more active toward inhibiting thrombin. The order of activity for the peptides containing analogs of Phe in the P3 position is (D)Phe>>(D)Tic>(L) Tic with conserved residues at P2=Pro and P1=DArg and variable L/D- amino-acids at P1'.
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