Exploring the chiral space within the active site of alpha-thrombin with a constrained mimic of D-Phe-Pro-Arg--design, synthesis, inhibitory activity, and X-ray structure of an enzyme-inhibitor complex.
An indolizidinone motif with strategically placed substitutents was designed and synthesized as a constrained mimic of D-Phe-Pro-Arg. Low nanomolar inhibition of alpha-thrombin validates the design elements in this inhibitor which also exhibits a 20-fold selectivity for thrombin versus trypsin. An X-ray crystal structure of the inhibitor with alpha-thrombin shows the expected interactions with key amino acids within the active site and some notable changes in positions.
Hanessian
S
S
Department of Chemistry, Université de Montréal, Québec, Canada. hanessia@ere.unmontreal.ca
Balaux
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E
Musil
D
D
Olsson
L L
LL
Nilsson
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I
D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D018716:Molecular Mimicry; D015335:Molecular Probes; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D013237:Stereoisomerism; D013917:Thrombin / Q000737:chemistry*
D004791:Enzyme Inhibitors; D015335:Molecular Probes; D009842:Oligopeptides; C077952:phenylalanyl-prolyl-arginine; D013917:Thrombin