Functionally active modulators targeting the LRRK2 WD40 repeat domain identified by FRASE-bot in CACHE Challenge #1

• DOI: 10.1039/d4sc07532c
• Publication Date: 2025-01-09T07:01:56Z
• Authors: Akhila Mettu; Marta Glavatskikh; Xiaowen Wang; Antonio Jesús Lar...; Fengling Li; Irene Chau; Suzanne Ackloo; Cheryl Arrowsmith; Albina Bolotokova; Pegah Ghiabi; Elisa Gibson; Levon Halabelian; Scott Houliston; Rachel J. Harding; Ashley Hutchinson; Peter Loppnau; Sumera Perveen; Almagul Seitova; Hong Zeng; Matthieu Schapira; Jean-Marc Taymans; Dmitri Kireev
• Keywords: Chemistry; [SDV]Life Sciences [q-bio]

Critical Assessment of Computational Hit-Finding Experiments (CACHE) Challenges emerged as real-life stress tests for computational hit-finding strategies. In CACHE Challenge #1, 23 participants contributed their original workflows to identify small-molecule ligands the WD40 repeat (WDR) LRRK2, a promising Parkinson's target. We applied FRASE-based robot (FRASE-bot), platform interaction-based screening allowing drastic reduction explorable chemical space and concurrent detection putative ligand-binding sites. two rounds, 84 compounds were procured experimental testing 8 confirmed bind LRRK2-WDR with dissociation constants (K d) ranging from 3 41 μM. To investigate functional effect WDR ligands, they tested ability modify LRRK2 activity markers in HEK293T cells. Two showed statistically significant increases kinase WT affected conformation major mutants.