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

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 for the WD40 repeat (WDR) of LRRK2, a promising Parkinson's target. We applied the FRASE-based hit-finding robot (FRASE-bot), a platform for interaction-based screening allowing a drastic reduction of the explorable chemical space and a concurrent detection of putative ligand-binding sites. In two screening rounds, 84 compounds were procured for experimental testing and 8 were confirmed to bind LRRK2-WDR with dissociation constants (<i>K</i> <sub>d</sub>) ranging from 3 to 41 μM. To investigate the functional effect of WDR ligands, they were tested for their ability to modify the LRRK2 activity markers in HEK293T cells. Two compounds showed statistically significant increases in the kinase activity of WT LRRK2, and two compounds affected the conformation and kinase activity of major LRRK2 mutants.

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Publication Details

Journal
Chemical Science
Published
2025-01-01
DOI
https://doi.org/10.1039/d4sc07532c
Citations
4
Primary Topic
Computational Drug Discovery Methods
Type
article
Field-Weighted Citation Impact
6.02

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article

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

P. Loppnau, Sumera Perveen, Levon Halabelian, Albina Bolotokova et al.
4 citations
Chemical Science
Computational Drug Discovery Methods
6.02
article

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

P. Loppnau, Sumera Perveen, Levon Halabelian, Albina Bolotokova, C. Arrowsmith, Irene Chau, Antonio Jesús Lara Ordóñez, Elisa Gibson, Rachel Harding, Dmitri Kireev, Almagul Seitova, Scott Houliston, Akhila Mettu, Fengling Li, Matthieu Schapira, Pegah Ghiabi, Jean‐Marc Taymans, Hong Zeng, Suzanne Ackloo, Xiaowen Wang, Ashley Hutchinson, Marta Glavatskikh
article en
4 citations

Abstract

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 for the WD40 repeat (WDR) of LRRK2, a promising Parkinson's target. We applied the FRASE-based hit-finding robot (FRASE-bot), a platform for interaction-based screening allowing a drastic reduction of the explorable chemical space and a concurrent detection of putative ligand-binding sites. In two screening rounds, 84 compounds were procured for experimental testing and 8 were confirmed to bind LRRK2-WDR with dissociation constants (<i>K</i> <sub>d</sub>) ranging from 3 to 41 μM. To investigate the functional effect of WDR ligands, they were tested for their ability to modify the LRRK2 activity markers in HEK293T cells. Two compounds showed statistically significant increases in the kinase activity of WT LRRK2, and two compounds affected the conformation and kinase activity of major LRRK2 mutants.

Chemical ScienceVol. 16(8)
University of North Carolina at Chapel Hill (US), University Health Network (CA), Inserm (FR), University of Toronto (CA), Université de Lille (FR), Princess Margaret Cancer Centre (CA), Structural Genomics Consortium (CA), Centre Hospitalier Universitaire de Lille (FR), University of Missouri (US)
Bristol-Myers Squibb, Pfizer, Bayer, University of Missouri, Genome Canada, Merck KGaA, Ontario Genomics, Ontario Genomics Institute, Agence Nationale de la Recherche, National Institutes of Health, Genentech, National Institute of General Medical Sciences
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Openalex Percentile: Top 5%
Computational Drug Discovery Methods
6.02
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