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Bolz SN, Salentin S, Jennings G, et al. Structural binding site comparisons reveal Crizotinib as a novel LRRK2 inhibitor. Comput Struct Biotechnol J. 2021;19:3674-3681doi: 10.1016/j.csbj.2021.06.013.
Bolz, S. N., Salentin, S., Jennings, G., Haupt, V. J., Sterneckert, J., & Schroeder, M. (2021). Structural binding site comparisons reveal Crizotinib as a novel LRRK2 inhibitor. Computational and structural biotechnology journal, 193674-3681. https://doi.org/10.1016/j.csbj.2021.06.013
Bolz, Sarah Naomi, et al. "Structural binding site comparisons reveal Crizotinib as a novel LRRK2 inhibitor." Computational and structural biotechnology journal vol. 19 (2021): 3674-3681. doi: https://doi.org/10.1016/j.csbj.2021.06.013
Bolz SN, Salentin S, Jennings G, Haupt VJ, Sterneckert J, Schroeder M. Structural binding site comparisons reveal Crizotinib as a novel LRRK2 inhibitor. Comput Struct Biotechnol J. 2021 Jun 10;19:3674-3681. doi: 10.1016/j.csbj.2021.06.013. eCollection 2021. PMID: 34285770; PMCID: PMC8258795.
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Comput Struct Biotechnol J. 2021 Jun 10;19:3674-3681. doi: 10.1016/j.csbj.2021.06.013. eCollection 2021.

Structural binding site comparisons reveal Crizotinib as a novel LRRK2 inhibitor.

Computational and structural biotechnology journal

Sarah Naomi Bolz, Sebastian Salentin, Gary Jennings, V Joachim Haupt, Jared Sterneckert, Michael Schroeder

Affiliations

  1. Biotechnology Center (BIOTEC), Technische Universität Dresden, Tatzberg 47/49, Dresden 01307, Germany.
  2. Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstr. 105, Dresden 01307, Germany.

PMID: 34285770 PMCID: PMC8258795 DOI: 10.1016/j.csbj.2021.06.013

Abstract

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

© 2021 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.

Keywords: Binding site; Crizotinib; Drug repositioning; LRRK2; Protein–ligand interactions; Structure-based screening

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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