Creating a more strategic small molecule biophysical hit characterization workflow

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS SLAS Discovery Pub Date : 2024-05-07 DOI:10.1016/j.slasd.2024.100159

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

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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.

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创建更具战略性的小分子生物物理命中表征工作流程。

为了确认高通量筛选工作中筛选出的目标参与，我们对 15 次不同的高通量筛选活动中筛选出的数百个目标进行了生物物理测定。通过分析这些筛选活动的生物物理检测结果，我们得出结论：首先在热转移检测（TSA）中确认活性，然后在表面等离子体共振（SPR）检测或温度相关强度变化（TRIC）检测中确认活性，这样就能更有策略地对筛选结果进行生物物理分析。为了了解这一新的工作流程如何影响最终结果的质量，我们使用四种化合物质量衡量标准对 TSA/SPR 或 TSA/TRIC 确认结果和未确认结果进行了比较：药物相似性定量估计 (QED)、泛分析干扰化合物 (PAINS)、杂合性和水溶性。总的来说，我们发现生物物理确认的命中化合物在化合物质量指标中的表现优于未确认的命中化合物，这表明我们的工作流程不仅确认了命中化合物的靶点参与，而且还富集了更高质量的命中化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

SLAS Discovery Chemistry-Analytical Chemistry

CiteScore

7.00

自引率

3.20%

发文量

审稿时长

39 days

期刊介绍： Advancing Life Sciences R&D: SLAS Discovery reports how scientists develop and utilize novel technologies and/or approaches to provide and characterize chemical and biological tools to understand and treat human disease. SLAS Discovery is a peer-reviewed journal that publishes scientific reports that enable and improve target validation, evaluate current drug discovery technologies, provide novel research tools, and incorporate research approaches that enhance depth of knowledge and drug discovery success. SLAS Discovery emphasizes scientific and technical advances in target identification/validation (including chemical probes, RNA silencing, gene editing technologies); biomarker discovery; assay development; virtual, medium- or high-throughput screening (biochemical and biological, biophysical, phenotypic, toxicological, ADME); lead generation/optimization; chemical biology; and informatics (data analysis, image analysis, statistics, bio- and chemo-informatics). Review articles on target biology, new paradigms in drug discovery and advances in drug discovery technologies. SLAS Discovery is of particular interest to those involved in analytical chemistry, applied microbiology, automation, biochemistry, bioengineering, biomedical optics, biotechnology, bioinformatics, cell biology, DNA science and technology, genetics, information technology, medicinal chemistry, molecular biology, natural products chemistry, organic chemistry, pharmacology, spectroscopy, and toxicology. SLAS Discovery is a member of the Committee on Publication Ethics (COPE) and was published previously (1996-2016) as the Journal of Biomolecular Screening (JBS).