In silico drug screening by using genome-wide association study data repurposed dabrafenib, an anti-melanoma drug, for Parkinson's disease.

Takeshi Uenaka,Tatsushi Toda,Motoi Kanagawa,Hideki Hayakawa,Pei-Chieng Cha,Hideki Mochizuki,Kazuhiro Kobayashi,Kousuke Baba,Yukinori Okada,Shiying Jiang,Wataru Satake

doi:10.1093/hmg/ddy279

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.

Highlights

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are primarily composed of aggregated α-synuclein in the neurons [1]
We considered that a total of 866 protein products from the 32 PD-risk genes and 834 genes in direct PPI have the possibility of involvement in PD pathogenesis
Among the 866 PD-risk/direct PPI genes, we found that 48 genes were targeted by 57 Food and Drug Administration (FDA)-approved drug families for other diseases, and considered these to be candidate disease-modifying drugs for PD (Supplementary Material, Fig. S1)

Summary

Results

We applied the in silico screening method [7] to identify diseasemodifying drugs for PD. Among the 866 PD-risk/direct PPI genes, we found that 48 genes were targeted by 57 FDA-approved drug families for other diseases, and considered these to be candidate disease-modifying drugs for PD (Supplementary Material, Fig. S1). Neuroprotective effects in in vitro or in vivo PD model have already been reported in 17 of the 57 FDA-approved drug families (∼30%) [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30] (Fig. 1). Our results suggest that this combinational analysis of GWAS-data and in silico database can efficiently identify drugs with neuroprotective effects

Introduction

Discussion

Materials and Methods