Synthesis and evaluation of new tripeptide phosphonate inhibitors of MMP-8 and MMP-2.
The phosphotryptophan derivative l-Pro-l-Leu-l-(P)Trp(OH)(2) (2b) was reported as the first example of left-hand-sideLeft-hand-side inhibitors: inhibitors that bind in the unprime region of the enzyme active site, in reference to the convention of drawing the unprimed residues of a peptide substrate on the left side. [R.P. Beckett et al., Drug Discov. Today 1 (1996) 16-26]. The opposite applies to right-hand-side inhibitors. phosphonate inhibitor of MMP-8. Its uncommon mode of binding to MMP-8 was mainly ascribed to the presence of the proline residue in P(3). Ten new analogues of 2b were obtained by replacement of the aminoterminal l-Pro with aminoacid residues bearing small side chains. Most of the new analogues show an increase of affinity for MMP-2 and MMP-8, and different profiles of selectivity. Computer simulations were performed to explain the effects of substitutions on the preferred mode of binding. They reveal that most of the new analogues are probably accommodated in the right, rather than left-hand side of MMP-8 active site.
Agamennone
Mariangela
M
Dipartimento di Scienze del Farmaco, Università G. d'Annunzio, Via dei Vestini 31, 66013 Chieti, Italy.
Campestre
Cristina
C
Preziuso
Serena
S
Consalvi
Valerio
V
Crucianelli
Marcello
M
Mazza
Fernando
F
Politi
Vincenzo
V
Ragno
Rino
R
Tortorella
Paolo
P
Gallina
Carlo
C
D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D020784:Matrix Metalloproteinase 8 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D063065:Organophosphonates; D011480:Protease Inhibitors; C413886:prolyl-leucyl-tryptophanphosphonic acid; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8