Discovery of LRRK2 inhibitors by using an ensemble of virtual screening methods

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2520-2527. doi: 10.1016/j.bmcl.2017.03.098. Epub 2017 Apr 2.

Abstract

In this paper, we present the results of a ligand- and structure-based virtual screen targeting LRRK2, a kinase that has been implicated in Parkinson's disease. For the ligand-based virtual screen, the structures of 12 competitor compounds were used as queries for a variety of 2D and 3D searches. The structure-based virtual screen relied on homology models of LRRK2, as no X-ray structure is currently available in the public domain. From the virtual screening, 662 compounds were purchased, of which 35 showed IC50 values below 10μM in wild-type and/or mutant LRRK2 (a hit rate of 5.3%). Of these 35 hits, four were deemed to have potential for medicinal chemistry follow-up.

Keywords: Homology modelling; LRRK2; Parkinson’s disease; Virtual screening.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Drug Design
  • Humans
  • Inhibitory Concentration 50
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Ligands
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*

Substances

  • Ligands
  • Protein Kinase Inhibitors
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2