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Quantifying Target Occupancy of Small Molecules Within Living Cells.
- Source :
-
Annual review of biochemistry [Annu Rev Biochem] 2020 Jun 20; Vol. 89, pp. 557-581. Date of Electronic Publication: 2020 Mar 24. - Publication Year :
- 2020
-
Abstract
- The binding affinity and kinetics of target engagement are fundamental to establishing structure-activity relationships (SARs) for prospective therapeutic agents. Enhancing these binding parameters for operative targets, while minimizing binding to off-target sites, can translate to improved drug efficacy and a widened therapeutic window. Compound activity is typically assessed through modulation of an observed phenotype in cultured cells. Quantifying the corresponding binding properties under common cellular conditions can provide more meaningful interpretation of the cellular SAR analysis. Consequently, methods for assessing drug binding in living cells have advanced and are now integral to medicinal chemistry workflows. In this review, we survey key technological advancements that support quantitative assessments of target occupancy in cultured cells, emphasizing generalizable methodologies able to deliver analytical precision that heretofore required reductionist biochemical approaches.
- Subjects :
- Bioluminescence Resonance Energy Transfer Techniques
Cell Survival drug effects
Cells, Cultured
Genes, Reporter
Humans
Kinetics
Optical Imaging methods
Small Molecule Libraries chemical synthesis
Small Molecule Libraries pharmacology
Structure-Activity Relationship
Chemistry, Pharmaceutical methods
Fluorescent Dyes chemistry
High-Throughput Screening Assays
Molecular Probe Techniques
Molecular Targeted Therapy methods
Subjects
Details
- Language :
- English
- ISSN :
- 1545-4509
- Volume :
- 89
- Database :
- MEDLINE
- Journal :
- Annual review of biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32208767
- Full Text :
- https://doi.org/10.1146/annurev-biochem-011420-092302