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Screening for positive allosteric modulators of biological targets
1Abbott Laboratories, R4PN/J35, 200 Abbott Park Road, Abbott Park, IL 60064, USA. duke.groebe@abbott.com
Drug Discovery Today
|June 24, 2006
Summary
Positive allosteric modulators offer targeted protein modulation for disease therapy. Current screening methods often miss these valuable therapeutic agents, necessitating improved discovery approaches.
Area of Science:
- Pharmacology
- Biochemistry
- Drug Discovery
Background:
- Positive allosteric modulators (PAMs) are increasingly recognized for their therapeutic potential in human diseases.
- PAMs offer advantages like specificity, selectivity, and activity limits, reducing in vivo off-target effects.
- Existing high-throughput screening (HTS) paradigms are not optimized for PAM discovery, leading to potential oversight of hits.
Purpose of the Study:
- To highlight the benefits and challenges of discovering positive allosteric modulators.
- To propose considerations for improving the identification of PAMs in screening campaigns.
- To discuss the role of ligand concentration and kinetic analysis in PAM screening.
Main Methods:
- Analysis of current screening paradigms for their suitability in identifying PAMs.
- Consideration of ligand concentration effects within screening assays.
- Application of kinetic schemes to understand modulator-protein interactions.
Main Results:
- Current screening methods may overlook serendipitously discovered PAMs.
- Simple adjustments to screening conditions, particularly ligand concentration, can facilitate PAM discovery.
- Kinetic modeling provides a framework for understanding PAM behavior and optimizing screening.
Conclusions:
- Improved screening strategies are needed to effectively identify positive allosteric modulators.
- Understanding ligand concentration and kinetics is crucial for successful PAM discovery.
- Optimized screening will enhance the therapeutic application of PAMs in human diseases.
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