Structural basis of the thrombin selectivity of a ligand that contains theconstrained arginine mimic (2S)-2-amino-(3S)-3-(1-carbamimidoyl-piperidin-3-yl)-propanoic acid at P1
Ls. Narasimhan et al., Structural basis of the thrombin selectivity of a ligand that contains theconstrained arginine mimic (2S)-2-amino-(3S)-3-(1-carbamimidoyl-piperidin-3-yl)-propanoic acid at P1, J MED CHEM, 43(3), 2000, pp. 361-368
We have studied the thrombin and trypsin complexed structures of a pair of
peptidomimetic thrombin inhibitors, containing different P1 fragments. The
first has arginine as its P1 fragment, and the second contains the constrai
ned arginine mimic (2S)-2-amino-(3S)-3-(1-carbamimidoyl-piperidin-3-yl)-pro
panoic acid (SAPA), a fragment known to enhance thrombin/trypsin selectivit
y of inhibitors. On the basis of an analysis of the nonbonded interactions
present in the structures of the trypsin and thrombin complexes of the two
inhibitors, the calculated accessible surfaces of the enzymes and inhibitor
s in the four complexes, data on known structures of trypsin complexes of i
nhibitors, and factor Xa inhibitory potency of these compounds, we conclude
that the ability of this arginine mimic to increase thrombin selectivity o
f an inhibitor is mediated by its differential interaction with the residue
at position 192 (chymotrypsinogen numbering). Thrombin has a glutamic acid
at residue 192, and trypsin has a glutamine. The analysis also suggests th
at this constrained arginine mimic, when present in an inhibitor, might enh
ance selectivity against other trypsin-like enzymes that have a glutamine a
t residue position 192.