Surface plasmon resonance using the catalytic domain of soluble guanylate cyclase allows the detection of enzyme activators

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1075-9. doi: 10.1016/j.bmcl.2014.01.015. Epub 2014 Jan 13.

Abstract

Soluble Guanylate Cyclase (sGC) is the receptor for the signalling agent nitric oxide (NO) and catalyses the production of the second messenger cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). The enzyme is an attractive drug target for small molecules that act in the cardiovascular and pulmonary systems, and has also shown to be a potential target in neurological disorders. We have discovered that 5-(indazol-3-yl)-1,2,4-oxadiazoles activate the enzyme in the absence of added NO and shown they bind to the catalytic domain of the enzyme after development of a surface plasmon resonance assay that allows the biophysical detection of intrinsic binding of ligands to the full length sGC and to a construct of the catalytic domain.

Keywords: Biophysical techniques; Enzyme activators; Nitric oxide; Soluble guanylate cyclase; Surface plasmon resonance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biocatalysis
  • Catalytic Domain / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Guanosine Monophosphate / biosynthesis
  • Guanylate Cyclase / antagonists & inhibitors
  • Guanylate Cyclase / metabolism*
  • Molecular Structure
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Soluble Guanylyl Cyclase
  • Structure-Activity Relationship
  • Surface Plasmon Resonance*

Substances

  • 5-(indazol-3-yl)-1,2,4-oxadiazole
  • Oxadiazoles
  • Receptors, Cytoplasmic and Nuclear
  • Guanosine Monophosphate
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase