title: Discovery of LRRK2 inhibitors using sequential in silico joint pharmacophore space (JPS) and ensemble docking.
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.
authors.affiliation: Acelot, Inc., 5385 Hollister Avenue, Suite 111, Santa Barbara, CA 93111, USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Lang
authors.affiliation: 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.
authors.forename: Soumya S
authors.initials: SS
authors.lastname: Ray
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Computer Science, University of California at Santa Barbara, Harold Frank Hall, Santa Barbara, CA 93106, USA. Electronic address: ambuj@cs.ucsb.edu.
authors.forename: Ambuj K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: 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.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D003198:Computer Simulation; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008958:Models, Molecular; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: Ensemble docking; In silico; Inhibitor; Joint pharmacophore space; LRRK2