Titre :

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

Auteur(s) :

Mettu, Akhila [Auteur]
University of Missouri [Columbia] [Mizzou]
Glavatskikh, Marta [Auteur]
University of North Carolina at Chapel Hill [NC, USA] [UNC]
Wang, Xiaowen [Auteur]
University of Missouri [Columbia] [Mizzou]
Lara Ordonez, Antonio Jesus [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Li, Fengling [Auteur]
Structural Genomics Consortium
Chau, Irene [Auteur]
Structural Genomics Consortium
Ackloo, Suzanne [Auteur]
Structural Genomics Consortium
Arrowsmith, Cheryl [Auteur]
Princess Margaret Hospital
Structural Genomics Consortium
University of Toronto
Bolotokova, Albina [Auteur]
Structural Genomics Consortium
Ghiabi, Pegah [Auteur]
Structural Genomics Consortium
Gibson, Elisa [Auteur]
Structural Genomics Consortium
Halabelian, Levon [Auteur]
University of Toronto
Structural Genomics Consortium
Houliston, Scott [Auteur]
Princess Margaret Hospital
Harding, Rachel J. [Auteur]
University of Toronto
Structural Genomics Consortium
Department of Pharmacology and Toxicology [Toronto]
Hutchinson, Ashley [Auteur]
Structural Genomics Consortium
Loppnau, Peter [Auteur]
Structural Genomics Consortium
Perveen, Sumera [Auteur]
Structural Genomics Consortium
Seitova, Almagul [Auteur]
Structural Genomics Consortium
Zeng, Hong [Auteur]
Structural Genomics Consortium
Schapira, Matthieu [Auteur]
University of Toronto
Structural Genomics Consortium
Taymans, Jean-Marc [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Kireev, Dmitri [Auteur]
University of North Carolina at Chapel Hill [NC, USA] [UNC]
University of Missouri [Columbia] [Mizzou]

Titre de la revue :

Chemical Science

Nom court de la revue :

Chem. Sci.

Numéro :

16

Pagination :

3430

Éditeur :

The Royal Society of Chemistry

Date de publication :

2025-02-28

ISSN :

2041-6520

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

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 ...
Lire la suite >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 (Kd) 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.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Projet ANR :

PARK-PEP: Ciblage de la phosphorylation de LRRK2 par peptides interférents en modèles experimentaux de la maladie de Parkinson

Établissement(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Lille Neurosciences & Cognition (LilNCog) - U 1172

Date de dépôt :

2025-03-22T22:00:49Z
2025-03-31T13:03:09Z