Structural binding site comparisons reveal Crizotinib as a novel LRRK2 inhibitor

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.