Structural Basis of the Thrombin Selectivity of a Ligand That Contains the Constrained Arginine Mimic (2S)-2-Amino-(3S)-3-(1-carbamimidoyl- piperidin-3-yl)-propanoic Acid at P1

• Published in: Journal of medicinal chemistry Vol. 43; no. 3; pp. 361 - 368
• Main Authors: Narasimhan, Lakshmi S, Rubin, J. Ronald, Holland, Debra R, Plummer, Janet S, Rapundalo, Stephen T, Edmunds, Jeremy E, St-Denis, Yves, Siddiqui, M. Arshad, Humblet, Christine
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 10.02.2000
• Subjects: Alanine - analogs & derivatives; Alanine - chemical synthesis; Alanine - chemistry; Amidines - chemical synthesis; Amidines - chemistry; Arginine - chemistry; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Crystallography, X-Ray; Factor Xa Inhibitors; Ligands; Medical sciences; Models, Molecular; Molecular Conformation; Molecular Mimicry; Pharmacology. Drug treatments; Structure-Activity Relationship; Thrombin - antagonists & inhibitors; Trypsin Inhibitors - chemical synthesis; Trypsin Inhibitors - chemistry; Angular nitrogen heterocycle; Thiazole derivatives; Non peptide compound; Thrombin; Anticoagulant; Selectivity; Modeling; Structure activity relation; Molecular model; Bicyclic compound; Chemical synthesis; Ungulata; Human; Molecular rigidity; Serine endopeptidases; Bovine; Enzyme; Peptidomimetic compound; Enzyme inhibitor; Inhibitor enzyme complex; Guanidines; In vitro; Peptidases; Vertebrata; Trypsin; Mammalia; Animal; Hydrolases; Carboxamide; Artiodactyla
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990216f

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 constrained arginine mimic (2S)-2-amino-(3S)-3-(1-carbamimidoyl-piperidin-3-yl)-propanoic acid (SAPA), a fragment known to enhance thrombin/trypsin selectivity 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 inhibitors in the four complexes, data on known structures of trypsin complexes of inhibitors, and factor Xa inhibitory potency of these compounds, we conclude that the ability of this arginine mimic to increase thrombin selectivity of 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 that this constrained arginine mimic, when present in an inhibitor, might enhance selectivity against other trypsin-like enzymes that have a glutamine at residue position 192.