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

Emanuela Gancia; Marcel De Groot; Brenda Burton; David E Clark

doi:10.1016/j.bmcl.2017.03.098

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.

Authors

Emanuela Gancia¹, Marcel De Groot², Brenda Burton², David E Clark²

Affiliations

¹ Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom. Electronic address: [email protected].
² Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.

PMID: 28408230
DOI: 10.1016/j.bmcl.2017.03.098

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