دورية أكاديمية
High-throughput mechanistic screening of non-equilibrium inhibitors by a fully automated data analysis pipeline in early drug-discovery
| العنوان: | High-throughput mechanistic screening of non-equilibrium inhibitors by a fully automated data analysis pipeline in early drug-discovery |
|---|---|
| المؤلفون: | Bharath Srinivasan, Juan Daniel Flórez Weidinger, Xiang Zhai, Guillaume Lemercier, Timothy Ikeda, Mark Brewer, Bairu Zhang, Stephan Heyse, Jonathan Wingfield, Stephan Steigele |
| المصدر: | SLAS Discovery, Vol 27, Iss 8, Pp 460-470 (2022) |
| بيانات النشر: | Elsevier, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Medicine (General) LCC:Biotechnology |
| مصطلحات موضوعية: | Mechanistic screening, Slow-onset inhibition, Irreversible inhibition, Mechanism-of-action, Data analysis, Drug screening, Medicine (General), R5-920, Biotechnology, TP248.13-248.65 |
| الوصف: | Recent efforts for increasing the success in drug discovery focus on an early, massive, and routine mechanistic and/or kinetic characterization of drug-target engagement as part of a design-make-test-analyze strategy. From an experimental perspective, many mechanistic assays can be translated into a scalable format on automation platforms and thereby enable routine characterization of hundreds or thousands of compounds.However, now the limiting factor to achieve such in-depth characterization at high-throughput becomes the quality-driven data analysis, the sheer scale of which outweighs the time available to the scientific staff of most labs. Therefore, automated analytical workflows are needed to enable such experimental scale-up. We have implemented such a fully automated workflow in Genedata Screener for time-dependent ligand-target binding analysis to characterize non-equilibrium inhibitors. The workflow automates Quality Control (QC) / data modelling and decision-making process in a staged analysis: (1) quality control of raw input data—fluorescence signal-based progress curves — featuring automated rejection of unsuitable measurements; (2) automated model selection — one-step versus two-step binding model — using statistical methods and biological validity rules; (3) result visualization in specific plots and annotated result tables, enabling the scientist to review large result sets efficiently and, at the same time, to rapidly identify and focus on interesting or unusual results; (4) an interactive user interface for immediate adjustment of automated decisions, where necessary.Applying this workflow to first-pass, high-throughput kinetic studies on kinase projects has allowed us to surmount previously rate-limiting manual analysis steps and boost productivity; and is now routinely embedded in a biopharma discovery research process. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2472-5552 |
| العلاقة: | http://www.sciencedirect.com/science/article/pii/S2472555222136956Test; https://doaj.org/toc/2472-5552Test |
| DOI: | 10.1016/j.slasd.2022.09.003 |
| الوصول الحر: | https://doaj.org/article/a2126a1a1f8f429598c4f15e9ed9a831Test |
| رقم الانضمام: | edsdoj.2126a1a1f8f429598c4f15e9ed9a831 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 24725552 |
|---|---|
| DOI: | 10.1016/j.slasd.2022.09.003 |