Developing Allosteric Chaperones for <i>GBA1</i>-Associated Disorders-An Integrated Computational and Experimental Approach.

ABSTRACT: Mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are associated with Gaucher disease and increased risk of Parkinson's disease. This study describes the discovery and characterization of novel allosteric pharmacological chaperones for GCase through an innovative computational approach combined with experimental validation. Utilizing virtual screening and structure-activity relationship optimization, researchers identified several compounds that significantly enhance GCase activity and stability across various cellular models, including patient-derived fibroblasts and neuronal cells harboring GBA1 mutations. Among these, compound 3 emerged as a lead candidate, demonstrating the ability to enhance GCase protein levels and enzymat

SUBMITTER: Montpeyo M 

PROVIDER: S-EPMC11720699 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature