期刊名称：Computational and Structural Biotechnology Journal
印刷版ISSN：2001-0370
出版年度：2021
卷号：19
页码：3674-3681
DOI：10.1016/j.csbj.2021.06.013
出版社：Computational and Structural Biotechnology Journal
摘要：Mutations in leucine-rich repeat kinase 2 (LRRK2) are a frequent cause of autosomal dominant Parkinson’s disease (PD) and have been associated with familial and sporadic PD. Reducing the kinase activity of LRRK2 is a promising therapeutic strategy since pathogenic mutations increase the kinase activity. Several small-molecule LRRK2 inhibitors are currently under investigation for the treatment of PD. However, drug discovery and development are always accompanied by high costs and a risk of late failure. The use of already approved drugs for a new indication, which is known as drug repositioning, can reduce the cost and risk. In this study, we applied a structure-based drug repositioning approach to identify new LRRK2 inhibitors that are already approved for a different indication. In a large-scale structure-based screening, we compared the protein–ligand interaction patterns of known LRRK2 inhibitors with protein–ligand complexes in the PDB. The screening yielded 6 drug repositioning candidates. Two of these candidates, Sunitinib and Crizotinib, demonstrated an inhibition potency (IC50) and binding affinity (K d ) in the nanomolar to micromolar range. While Sunitinib has already been known to inhibit LRRK2, Crizotinib is a novel LRRK2 binder. Our results underscore the potential of structure-based methods for drug discovery and development. In light of the recent breakthroughs in cryo-electron microscopy and structure prediction, we believe that structure-based approaches like ours will grow in importance.
关键词：Protein–ligand interactions ; Drug repositioning ; Binding site ; LRRK2 ; Crizotinib ; Structure-based screening
