Discovery of LRRK2 inhibitors using sequential in silico joint pharmacophore space (JPS) and ensemble docking

Christian A Lang; Soumya S Ray; Min Liu; Ambuj K Singh; Gregory D Cuny

doi:10.1016/j.bmcl.2015.04.027

Discovery of LRRK2 inhibitors using sequential in silico joint pharmacophore space (JPS) and ensemble docking

Bioorg Med Chem Lett. 2015 Jul 1;25(13):2713-9. doi: 10.1016/j.bmcl.2015.04.027. Epub 2015 Apr 16.

Authors

Christian A Lang¹, Soumya S Ray², Min Liu³, Ambuj K Singh⁴, Gregory D Cuny⁵

Affiliations

¹ Acelot, Inc., 5385 Hollister Avenue, Suite 111, Santa Barbara, CA 93111, USA.
² Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne St, 4th Floor, Cambridge, MA 02139, USA. Electronic address: soumya.ray@schrodinger.com.
³ Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne St, 4th Floor, Cambridge, MA 02139, USA.
⁴ Department of Computer Science, University of California at Santa Barbara, Harold Frank Hall, Santa Barbara, CA 93106, USA. Electronic address: ambuj@cs.ucsb.edu.
⁵ Department of Pharmacological and Pharmaceutical Sciences, University of Houston, College of Pharmacy, 549A Science and Research Bldg 2, Houston, TX 77204, USA. Electronic address: gdcuny@central.uh.edu.

PMID: 25998502
DOI: 10.1016/j.bmcl.2015.04.027

Abstract

Joint pharmacophore space (JPS), ensemble docking and sequential JPS-ensemble docking were used to select three panels of compounds (10 per panel) for evaluation as LRRK2 inhibitors. These computational methods identified four LRRK2 inhibitors with IC50 values <12μM. The sequential JPS-ensemble docking predicted the majority of active hits. One of the inhibitors (Z-8205) identified using this method was also found to inhibit the G2019S mutant of LRRK2 25-fold better than wild-type enzyme. This bias for the G2019S mutant is proposed to arise from an interaction with S2019 in this form of the enzyme. In addition, Z-8205 was found to only inhibit one other kinase when profiled against a panel of 97 kinases at 10μM.

Keywords: Ensemble docking; In silico; Inhibitor; Joint pharmacophore space; LRRK2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Substitution
Binding Sites
Computer Simulation
Drug Discovery
High-Throughput Screening Assays
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Models, Molecular
Mutant Proteins / antagonists & inhibitors
Mutant Proteins / chemistry
Mutant Proteins / genetics
Parkinson Disease / enzymology
Parkinson Disease / genetics
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / genetics
Structural Homology, Protein
Structure-Activity Relationship

Substances

Mutant Proteins
Protein Kinase Inhibitors
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Protein Serine-Threonine Kinases