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1Department of Pharmaceutical Chemistry, University of California-San Francisco, 1700 4th St., Byers Hall Room 508D, San Francisco, CA 94158, USA. shoichet@cgl.ucsf.edu
Drug Discovery Today
|June 24, 2006
Summary
Many high-throughput screening hits are non-drug-like due to compound aggregation. These aggregates form particles in buffers, inhibiting protein targets and complicating drug discovery efforts.
Area of Science:
- Biochemistry
- Drug Discovery
- Chemical Biology
Background:
- High-throughput screening (HTS) frequently identifies non-drug-like compounds.
- Artifactual hits exhibit steep dose-response curves and assay sensitivity.
- Common artifact mechanisms include reactivity, light absorption, and redox effects.
Purpose of the Study:
- To review aggregation-based inhibition as a common artifact in HTS.
- To explain the biophysical basis of aggregation-induced artifactual inhibition.
- To discuss the implications of aggregation in drug discovery.
Main Methods:
- Literature review focusing on aggregation-based inhibition mechanisms.
- Analysis of biophysical principles governing molecular aggregation in aqueous buffers.
- Discussion of detection methods and biological relevance of artifactual compounds.
Main Results:
- Organic molecules can aggregate into particles at micromolar concentrations in aqueous buffers.
- These aggregates can sequester and inhibit protein targets, mimicking true inhibition.
- Aggregation-based inhibition is a common source of false positives in HTS.
Conclusions:
- Aggregation-based inhibition is a significant challenge in HTS campaigns.
- Understanding aggregation is crucial for distinguishing true hits from artifacts.
- Biophysical properties, not just chemical structure, dictate compound behavior in assays.
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