HTS reporter displacement assay for fragment screening and fragment evolution toward leads with optimized binding kinetics, binding selectivity, and thermodynamic signature
Abstract
Parameters such as residence time, kinetic selectivity, and thermodynamic signature are more and more under debate as optimization objectives within fragment-based lead discovery. However, broad implementation of these parameters is hampered by the lack of technologies that give rapid access to binding kinetics and thermodynamic information for large amounts of compound-target interactions. Here, the authors describe a technology--the reporter displacement assay--that is capable of opening this bottleneck and of supporting data-driven design of lead compounds with tailor-made residence time, kinetic selectivity, and thermodynamic signature.
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SAHA and TSA selectivity profiles extended well beyond HDAC1 and HDAC2.
“but their selectivity profiles extended well beyond these isoforms as reported previously (12, 13, 26, 29, 30, 38).”
From Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability (2013) · cites this paper as [30]
Previous studies investigating the role of HDACi on gene expression changes in HL60 cells are in agreement with the observed gene expression changes.
“This is in agreement with previous studies investigating the role of HDACiongeneexpression changes in HL60 cells (2, 29, 30, 35, 43).”
From Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability (2013) · cites this paper as [30]
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References 30 · Cited by 51
- Authors
- Neumann, L., von König, K., & Ullmann, D.
- ORCID
- Ullmann, Dirk
- Venue
- Methods in Enzymology
- Publisher
- Elsevier
- Published
- 2011
- Volume
- 493
- Pages
- 299-320
- ISSN
- 0076-6879 (ISSN-L)
- OpenAlex
- W1525851782
- Cited by
- 51
- References
- 30
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 11 · 2015: 8 · 2014: 3 · 2013: 6 · 2012: 3
- FWCI
- 1.92
- Type
- book chapter
- Language
- en
- Open access
- closed
- Locations
- Methods in enzymology on CD-ROM/Methods in enzymology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › thermodynamics and calorimetric analyses
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Keywords
- fragment-based drug discovery, binding kinetics, binding thermodynamics, kinetic selectivity, residence time, fragment screening, compound-target interactions
- MeSH terms
- Drug Evaluation, Preclinical, Kinetics, Protein Binding, Thermodynamics, Drug Design, Mitogen-Activated Protein Kinase 14
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