The reversed binding of beta-phenethylamine inhibitors of DPP-IV: X-ray structures and properties of novel fragment and elaborated inhibitors

Bioorg Med Chem Lett. 2006 Mar 15;16(6):1744-8. doi: 10.1016/j.bmcl.2005.11.103. Epub 2006 Jan 11.

Abstract

The co-crystal structure of beta-phenethylamine fragment inhibitor 5 bound to DPP-IV revealed that the phenyl ring occupied the proline pocket of the enzyme. This finding provided the basis for a general hypothesis of a reverse binding mode for beta-phenethylamine-based DPP-IV inhibitors. Novel inhibitor design concepts that obviate substrate-like structure-activity relationships (SAR) were thereby enabled, and novel, potent inhibitors were discovered.

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Dipeptidyl Peptidase 4 / chemistry*
  • Dipeptidyl Peptidase 4 / metabolism*
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Phenethylamines* / chemistry
  • Phenethylamines* / metabolism
  • Proline / chemistry
  • Protein Binding
  • Structure-Activity Relationship
  • Swine

Substances

  • Enzyme Inhibitors
  • Phenethylamines
  • phenethylamine
  • Proline
  • Dipeptidyl Peptidase 4