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In silico drug screening by using genome-wide association study data repurposed dabrafenib, an anti-melanoma drug, for Parkinson's disease
- Source :
- Human Molecular Genetics
- Publication Year :
- 2018
- Publisher :
- Oxford University Press (OUP), 2018.
-
Abstract
- Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss. At present, there are no drugs that stop the progression of PD. As with other multifactorial genetic disorders, genome-wide association studies (GWASs) found multiple risk loci for PD, although their clinical significance remains uncertain. Here, we report the identification of candidate drugs for PD by a method using GWAS data and in silico databases. We identified 57 Food and Drug Administration-approved drug families as candidate neuroprotective drugs for PD. Among them, dabrafenib, which is known as a B-Raf kinase inhibitor and is approved for the treatment of malignant melanoma, showed remarkable cytoprotective effects in neurotoxin-treated SH-SY5Y cells and mice. Dabrafenib was found to inhibit apoptosis, and to enhance the phosphorylation of extracellular signal-regulated kinase (ERK), and inhibit the phosphorylation of c-Jun NH2-terminal kinase. Dabrafenib targets B-Raf, and we confirmed a protein–protein interaction between B-Raf and Rit2, which is coded by RIT2, a PD risk gene in Asians and Caucasians. In RIT2-knockout cells, the phosphorylation of ERK was reduced, and dabrafenib treatment improved the ERK phosphorylation. These data indicated that dabrafenib exerts protective effects against neurotoxicity associated with PD. By using animal model, we confirmed the effectiveness of this in silico screening method. Furthermore, our results suggest that this in silico drug screening system is useful in not only neurodegenerative diseases but also other common diseases such as diabetes mellitus and hypertension.
- Subjects :
- 0301 basic medicine
Drug
MAPK/ERK pathway
Proto-Oncogene Proteins B-raf
mice
MAP Kinase Signaling System
media_common.quotation_subject
In silico
Drug Evaluation, Preclinical
Genome-wide association study
Antineoplastic Agents
Apoptosis
Pharmacology
Biology
03 medical and health sciences
parkinson disease
Oximes
Genetics
medicine
melanoma
Animals
Humans
Computer Simulation
Protein Interaction Maps
drug screening
dabrafenib
Association Studies Article
Molecular Biology
Drug Approval
Protein Kinase Inhibitors
Genetics (clinical)
media_common
Monomeric GTP-Binding Proteins
genome-wide association study
Kinase
phosphorylation
Melanoma
Dopaminergic Neurons
Neurotoxicity
Imidazoles
JNK Mitogen-Activated Protein Kinases
Dabrafenib
General Medicine
medicine.disease
030104 developmental biology
Neuroprotective Agents
Cytoprotection
Databases, Chemical
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 09646906
- Volume :
- 27
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....674bdc58002db3e1449df2ddbfc8ee48