Genetic variations/Mutations in Leucine-rich repeat kinase 2 (LRRK2) have been linked to the increased risk of developing Parkinson's disease. In particular, the G2019S mutation at LRRK2 kinase domain, is the most frequent mutation in the Caucasian population. Studies have shown that the kinase activity of LRRK2 is closely associated with Parkinson's disease pathophysiogenesis. Therefore, it would be highly desirable to develop selective and brain penetrant LRRK2 inhibitors by modulating LRRK2 kinase activity.In this study, we described the integration of fragment and high throughput screening, and the design of LRRK2 surrogate for X-ray crystallography. Our analysis suggests that fragment screening and HTS results are complementary in a drug discovery project. We also want to demonstrate that a surrogate kinase with mutations carefully chosen is a pragmatic and yet meaningful way to obtain structural information to guide ligand design. As a result, we now have selective and brain penetrant LRRK2 inhibitors which can be used to interrogate LRRK2 biology and study its role in Parkinson's disease.

Screening and structural strategies for the design of selective Leucine-rich repeat kinase 2 (LRRK2) inhibitors

248th National Meeting (2014)

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