Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of β-Glucocerebrosidase Article Swipe
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1021/acs.jmedchem.4c00702
· OA: W4400093141
β-Glucocerebrosidase (GBA/GCase) mutations leading to misfolded protein cause Gaucher's disease and are a major genetic risk factor for Parkinson's disease and dementia with Lewy bodies. The identification of small molecule pharmacological chaperones that can stabilize the misfolded protein and increase delivery of degradation-prone mutant GCase to the lysosome is a strategy under active investigation. Here, we describe the first use of fragment-based drug discovery (FBDD) to identify pharmacological chaperones of GCase. The fragment hits were identified by using X-ray crystallography and biophysical techniques. This work led to the discovery of a series of compounds that bind GCase with nM potency and positively modulate GCase activity in cells.
