Journal
SLAS DISCOVERY
Volume 26, Issue 10, Pages 1355-1364Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/24725552211030897
Keywords
butyrylcholinesterase; BChE inhibitors; colorimetric BChE assay; qHTS; molecular docking
Funding
- Intramural Research Program of the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health
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The screening for BChE inhibitors has yielded a group of potential new inhibitors, some of which have shown selectivity and unique binding modes compared to AChE inhibitors. This study provides insights into the development of novel therapeutic approaches for Alzheimer's disease targeting BChE.
Butyrylcholinesterase (BChE) is a nonspecific cholinesterase enzyme that hydrolyzes choline-based esters. BChE plays a critical role in maintaining normal cholinergic function like acetylcholinesterase (AChE) through hydrolyzing acetylcholine (ACh). Selective BChE inhibition has been regarded as a viable therapeutic approach in Alzheimer's disease. As of now, a limited number of selective BChE inhibitors are available. To identify BChE inhibitors rapidly and efficiently, we have screened 8998 compounds from several annotated libraries against an enzyme-based BChE inhibition assay in a quantitative high-throughput screening (qHTS) format. From the primary screening, we identified a group of 125 compounds that were further confirmed to inhibit BChE activity, including previously reported BChE inhibitors (e.g., bambuterol and rivastigmine) and potential novel BChE inhibitors (e.g., pancuronium bromide and NNC 756), representing diverse structural classes. These BChE inhibitors were also tested for their selectivity by comparing their IC50 values in BChE and AChE inhibition assays. The binding modes of these compounds were further studied using molecular docking analyses to identify the differences between the interactions of these BChE inhibitors within the active sites of AChE and BChE. Our qHTS approach allowed us to establish a robust and reliable process to screen large compound collections for potential BChE inhibitors.
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