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Hitting a moving target: targeting transient protein states.
Matthias R Bauer1, Frank M Boeckler
1Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
Structure (London, England : 1993)
|December 10, 2013
Summary
Researchers found that inhibitors targeting the MDM2/p53 interaction can bind to a specific protein segment. This discovery offers a new strategy for designing potent and selective protein-protein interaction inhibitors.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- The MDM2/p53 interaction is a key target for cancer therapy.
- Developing selective inhibitors for protein-protein interactions (PPIs) remains challenging.
Purpose of the Study:
- To investigate novel strategies for designing inhibitors of the MDM2/p53 interaction.
- To explore the potential of targeting transient protein states for improved inhibitor design.
Main Methods:
- Structural analysis of the MDM2 lid region.
- Design and testing of inhibitors targeting transiently folded protein states.
Main Results:
- Inhibitors can be designed to interact with a transiently folded α-helical segment of the MDM2 lid region.
- This interaction enhances inhibitor affinity and/or selectivity.
Conclusions:
- Targeting transient protein states is a viable strategy for designing effective PPI inhibitors.
- This approach could lead to improved therapeutic agents for targeting the MDM2/p53 pathway.
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