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Functionally active modulators targeting the LRRK2 WD40 repeat domain identified by FRASE-bot in CACHE Challenge #1.
Akhila Mettu1, Marta Glavatskikh2, Xiaowen Wang1
1University of Missouri - Columbia, Department of Chemistry USA dmitri.kireev@missouri.edu.
Chemical Science
|January 29, 2025
Summary
Computational hit-finding strategies were tested in the CACHE Challenge. The FRASE-bot identified 8 LRRK2-WDR binders, with 2 compounds modulating Parkinson
Area of Science:
- Computational chemistry and drug discovery
- Neuroscience and Parkinson's disease research
Background:
- The WD40 repeat (WDR) of Leucine-Rich Repeat Kinase 2 (LRRK2) is a key target for Parkinson's disease therapeutics.
- Computational hit-finding strategies require rigorous validation through real-world challenges.
Purpose of the Study:
- To assess the efficacy of computational hit-finding workflows in identifying LRRK2-WDR ligands.
- To evaluate the performance of the FRASE-based hit-finding robot (FRASE-bot) in a competitive challenge setting.
- To investigate the functional impact of identified ligands on LRRK2 activity.
Main Methods:
- Application of the FRASE-bot, an interaction-based screening platform, for hit identification.
- Procurement and experimental testing of 84 selected compounds.
- Biochemical assays to determine binding affinity (Kd) and cellular assays to assess LRRK2 activity modulation.
Main Results:
- Eight compounds were confirmed to bind the LRRK2-WDR domain, with dissociation constants ranging from 3 to 41 μM.
- Two identified compounds demonstrated a statistically significant increase in wild-type LRRK2 kinase activity.
- Two compounds modulated the conformation and kinase activity of key LRRK2 mutants.
Conclusions:
- The FRASE-bot successfully identified validated binders for the LRRK2-WDR target.
- Identified ligands show potential for modulating LRRK2 activity, offering therapeutic avenues for Parkinson's disease.
- The Critical Assessment of Computational Hit-Finding Experiments (CACHE) challenge provides a valuable platform for validating computational methods.
