Creating a more strategic small molecule biophysical hit characterization workflow
Year: 2024
Type: article
Abstract: To confirm target engagement of hits from our high-throughput screening efforts, we ran biophysical assays on several hundreds of hits from 15 different high-throughput screening campaigns. Analyzing the biophysical assay results from these screening campaigns led us to conclude that we could be more strategic in our biophysical analysis of hits by first confirming activity in a thermal shift assay (TSA) and then confirming activity in either a surface plasmon resonance (SPR) assay or a temperature-related intensity change (TRIC) assay. To understand how this new workflow shapes the quality of the final hits, we compared TSA/SPR or TSA/TRIC confirmed and unconfirmed hits to one another using four measures of compound quality: quantitative estimate of drug-likeness (QED), Pan-Assay Interference Compounds (PAINS), promiscuity, and aqueous solubility. In general, we found that the biophysically confirmed hits performed better in the compound quality metrics than the unconfirmed hits, demonstrating that our workflow not only confirmed target engagement of the hits but also enriched for higher quality hits.
Source: SLAS DISCOVERY
Authors: Christopher Fotsch, Debaleena Basu, Ryan Case, Qing Chen, Pratibha C. Koneru, Mei-Chu Lo, Rachel Ngo, Pooja Sharma, Amit Vaish, Xiang Yi, Stephan G. Zech, Peter Hodder
Institution: Amgen (United States)
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $1,800
OpenAlex ID: W4396690648