Structural Characterization of LRRK2 Inhibitors

J Med Chem. 2015 May 14;58(9):3751-6. doi: 10.1021/jm5018779. Epub 2015 May 1.

Abstract

Kinase inhibition is considered to be an important therapeutic target for LRRK2 mediated Parkinson's disease (PD). Many LRRK2 kinase inhibitors have been reported but have yet to be optimized in order to qualify as drug candidates for the treatment of the disease. In order to start a structure-function analysis of such inhibitors, we mutated the active site of Dictyostelium Roco4 kinase to resemble LRRK2. Here, we show saturation transfer difference (STD) NMR and the first cocrystal structures of two potent in vitro inhibitors, LRRK2-IN-1 and compound 19, with mutated Roco4. Our data demonstrate that this system can serve as an excellent tool for the structural characterization and optimization of LRRK2 inhibitors using X-ray crystallography and NMR spectroscopy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Dictyostelium / enzymology*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Molecular Docking Simulation
  • Morpholines / chemistry
  • Point Mutation
  • Protein Binding
  • Protein Conformation
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Serine-Threonine Kinases / genetics
  • Protozoan Proteins / antagonists & inhibitors
  • Protozoan Proteins / chemistry*
  • Protozoan Proteins / genetics
  • Pyrimidines / chemistry

Substances

  • Morpholines
  • Protozoan Proteins
  • Pyrimidines
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases

Associated data

  • PDB/4YZM
  • PDB/4YZN