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Binding Kinetics Survey of the Drugged Kinome
- Source :
- Journal of the American Chemical Society. 140:15774-15782
- Publication Year :
- 2018
- Publisher :
- American Chemical Society (ACS), 2018.
-
Abstract
- Target residence time is emerging as an important optimization parameter in drug discovery, yet target and off-target engagement dynamics have not been clearly linked to the clinical performance of drugs. Here we developed high-throughput binding kinetics assays to characterize the interactions of 270 protein kinase inhibitors with 40 clinically relevant targets. Analysis of the results revealed that on-rates are better correlated with affinity than off-rates and that the fraction of slowly dissociating drug-target complexes increases from early/preclinical to late stage and FDA-approved compounds, suggesting distinct contributions by each parameter to clinical success. Combining binding parameters with PK/ADME properties, we illustrate in silico and in cells how kinetic selectivity could be exploited as an optimization strategy. Furthermore, using bio- and chemoinformatics we uncovered structural features influencing rate constants. Our results underscore the value of binding kinetics information in rational drug design and provide a resource for future studies on this subject.
- Subjects :
- 0301 basic medicine
In silico
Kinetics
Computational biology
01 natural sciences
Biochemistry
Catalysis
03 medical and health sciences
Colloid and Surface Chemistry
Drug Discovery
Humans
Kinome
Binding site
Protein Kinase Inhibitors
ADME
Binding Sites
Molecular Structure
010405 organic chemistry
Chemistry
Drug discovery
Phosphotransferases
General Chemistry
Receptor–ligand kinetics
0104 chemical sciences
030104 developmental biology
Cheminformatics
Subjects
Details
- ISSN :
- 15205126 and 00027863
- Volume :
- 140
- Database :
- OpenAIRE
- Journal :
- Journal of the American Chemical Society
- Accession number :
- edsair.doi.dedup.....a0ce204f68876cd7a87c21605ba73aaa