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

Bioorg Med Chem Lett. 2000 Feb 7;10(3):243-7. doi: 10.1016/s0960-894x(99)00669-1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Models, Molecular
  • Molecular Mimicry*
  • Molecular Probes
  • Molecular Structure
  • Oligopeptides / chemistry*
  • Stereoisomerism
  • Thrombin / chemistry*

Substances

  • Enzyme Inhibitors
  • Molecular Probes
  • Oligopeptides
  • phenylalanyl-prolyl-arginine
  • Thrombin