Structural basis for the selective inhibition of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) by a selenium-containing inhibitor with chloro-aminopyridine as a basic group

Bioorg Med Chem Lett. 2018 Jul 15;28(13):2256-2260. doi: 10.1016/j.bmcl.2018.05.042. Epub 2018 May 23.

Abstract

Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) is a target molecule for treating thromboembolic disorders. We previously reported that design and synthesis of compound 1 containing a selenol group and chloloaminopyridine. Compound 1 showed high inhibitory activity towards TAFIa, with a high degree of selectivity for TAFIa over carboxypeptidase N (CPN). Here we report investigation of this selectivity. To obtain co-crystal of 1/pp-CPB (a surrogate of TAFIa), we synthesized protected compound 5 as a stabilized precursor of 1. The X-ray crystal structure and docking study indicated that the Cl substituent is accommodated in the pp-CPB specific pocket whereas CPN has no identical pocket. This is important information for the design of drugs targeting TAFIa with high selectivity.

Keywords: CPN; Crystal structure; Organo-selenium; Selenium compound; TAFIa inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemical synthesis
  • Aminopyridines / chemistry*
  • Animals
  • Binding Sites
  • Carboxypeptidase B / antagonists & inhibitors
  • Carboxypeptidase B / chemistry
  • Carboxypeptidase B2 / antagonists & inhibitors*
  • Humans
  • Hydrogen Bonding
  • Lysine Carboxypeptidase / antagonists & inhibitors
  • Molecular Docking Simulation
  • Organoselenium Compounds / chemical synthesis
  • Organoselenium Compounds / chemistry*
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Swine

Substances

  • Aminopyridines
  • Organoselenium Compounds
  • Protease Inhibitors
  • Carboxypeptidase B
  • CPB2 protein, human
  • Carboxypeptidase B2
  • Lysine Carboxypeptidase