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Updated: Jul 4, 2026
06:26
Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery
Published on: May 16, 2021
Shape shifting leads to small-molecule allosteric drug discovery
Sarah H Lawrence1, Ursula D Ramirez, Lei Tang
1Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Chemistry & Biology
|June 19, 2008
Summary
Researchers discovered a novel strategy for enzyme inhibition by targeting morpheeins, like porphobilinogen synthase (PBGS). A specific compound was found to convert active PBGS octamers to inactive hexamers, offering new therapeutic possibilities.
Area of Science:
- Biochemistry
- Enzymology
- Allosteric Regulation
Background:
- Morpheins represent a recently identified mode of allosteric enzyme regulation, involving shifts in oligomeric states.
- Porphobilinogen synthase (PBGS) exhibits an oligomeric equilibrium involving active octamers and less active hexamers.
Purpose of the Study:
- To investigate the morphein-based allosteric regulation of PBGS.
- To identify small molecules that can modulate the PBGS oligomeric equilibrium for potential therapeutic applications.
Main Methods:
- In silico docking was employed to screen a small-molecule library for potential binders to a hexamer-specific allosteric site on PBGS.
- In vitro assays were used to test selected compounds and determine their effect on PBGS oligomeric state and activity.
Main Results:
- A novel allosteric site specific to PBGS hexamers was identified.
- One screened compound demonstrated species-specific inhibition by inducing the conversion of active PBGS octamers to inactive hexamers.
Conclusions:
- The study validates a strategy for discovering inhibitors targeting morpheein proteins.
- This approach holds promise for developing new therapeutics by modulating enzyme activity through allosteric control of oligomeric states.
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