Development of LRRK2 inhibitors through computational strategies: a promising avenue for Parkinson's disease

Drug Discov Today. 2025 Sep;30(9):104446. doi: 10.1016/j.drudis.2025.104446. Epub 2025 Aug 13.

Abstract

Parkinson's disease (PD) is a prevalent neurodegenerative disorder that remains incurable. Leucine-rich repeat kinase 2 (LRRK2) has a pivotal role in PD pathogenesis, making it a promising therapeutic target. Thus, there is an urgent need to develop structurally diverse, highly selective, blood-brain barrier (BBB)-permeable LRRK2 inhibitors. Computer-aided and artificial intelligence (AI)-driven drug design methods have shown significant advantages in the discovery of LRRK2 inhibitors. Building upon a systematic review of structural characteristics, biological functions, and molecular mechanisms of LRRK2, in this review, we summarize recent advances in LRRK2 inhibitor development, highlighting the pivotal role of computational approaches in accelerating inhibitor discovery.

Keywords: AI-driven drug design; LRRK2 inhibitors; Parkinson’s disease; computer-aided drug design.

Publication types

  • Systematic Review

MeSH terms

  • Animals
  • Artificial Intelligence
  • Blood-Brain Barrier / metabolism
  • Drug Design
  • Drug Development / methods
  • Drug Discovery / methods
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / antagonists & inhibitors
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / metabolism
  • Parkinson Disease* / drug therapy
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use

Substances

  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • LRRK2 protein, human
  • Protein Kinase Inhibitors