The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson's Disease

: Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of people worldwide. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for PD. Elevated LRRK2 kinase activity is found in idiopathic and familial PD cases. LRRK2 mutations are involved in multiple PD pathogeneses, including dysregulation of mitochondrial homeostasis, ciliogenesis, etc. Here, we provide a comprehensive overview of the biological function, structure, and mutations of LRRK2. We also examine recent advances and challenges in developing LRRK2 inhibitors and address prospective protein-based targeting strategies. The binding mechanisms, structure-activity relationships, and pharmacokinetic features of inhibitors are emphasized to provide a comprehensive compendium on the rational design of LRRK2 inhibitors. We hope that this publication can serve as a guide for designing novel LRRK2 inhibitors based on the summarized facts and perspectives.