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A Method for Selecting Structure-switching Aptamers Applied to a Colorimetric Gold Nanoparticle Assay
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Molecular chameleons adaptability in target binding
Guanhong Bu1, Måns Eriksson1, Emma Rova Danelius1
1Department of Chemistry, University of California Riverside, 501 Big Springs Rd., Riverside, California 92521, USA.
Structural Dynamics (Melville, N.Y.)
|August 18, 2025
Summary
Macrocycles, or molecular chameleons, can target previously undruggable proteins. Their conformational flexibility allows adaptation to various targets, aiding drug development for diseases like Hepatitis C, COVID-19, and cancer.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Drug Discovery
Background:
- Up to 85% of human therapeutic proteomes are undruggable by traditional small molecules.
- Macrocycles offer potential for modulating challenging biological targets.
- These molecules exhibit conformational flexibility, acting as 'molecular chameleons'.
Purpose of the Study:
- To explore the conformational adaptability of macrocycles in target binding.
- To investigate three known macrocyclic drugs: paritaprevir, grazoprevir, and simeprevir.
- To assess binding to drug transporters and COVID-19 related proteins.
Main Methods:
- Molecular docking of experimental crystal, solution, and target-bound structures.
- Analysis of conformational changes upon protein binding.
- Comparison across multiple protein targets.
Main Results:
- The macrocyclic core's conformational class dictates overall pharmacophore conformation.
- This 'chameleonic group' influences conformational changes necessary for protein binding.
- Identified specific binding patterns relevant to drug transporters and viral proteins.
Conclusions:
- Macrocycle conformational adaptability is key to their broad target engagement.
- Insights guide rational drug optimization for macrocyclic therapeutics.
- Provides a basis for repurposing Hepatitis C inhibitors for COVID-19 and cancer therapies.
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