Discovery and structural analyses of S-adenosyl-L-homocysteine hydrolase inhibitors based on non-adenosine analogs

Bioorg Med Chem. 2015 Aug 1;23(15):4952-4969. doi: 10.1016/j.bmc.2015.05.018. Epub 2015 May 19.

Abstract

Optimization of a new series of S-adenosyl-L-homocysteine hydrolase (AdoHcyase) inhibitors based on non-adenosine analogs led to very potent compounds 14n, 18a, and 18b with IC50 values of 13 ± 3, 5.0 ± 2.0, and 8.5 ± 3.1 nM, respectively. An X-ray crystal structure of AdoHcyase with NAD(+) and 18a showed a novel open form co-crystal structure. 18a in the co-crystals formed intramolecular eight membered ring hydrogen bond formations. A single crystal X-ray structure of 14n also showed an intramolecular eight-membered ring hydrogen bond interaction.

Keywords: Homocysteine; Intramolecular eight-membered ring hydrogen bond interaction; S-Adenosyl-l-homocysteine hydrolase; X-ray crystal structure; cis-Amide.

MeSH terms

  • Adenosine / chemistry
  • Adenosylhomocysteinase / antagonists & inhibitors*
  • Adenosylhomocysteinase / genetics
  • Adenosylhomocysteinase / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Humans
  • Hydrogen Bonding
  • Isomerism
  • Molecular Conformation
  • Molecular Dynamics Simulation
  • NAD / chemistry
  • NAD / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Recombinant Proteins
  • NAD
  • Adenosylhomocysteinase
  • Adenosine