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Discovering high-affinity ligands for proteins: SAR by NMR
S B Shuker1, P J Hajduk, R P Meadows
1Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, IL 60064, USA.
Science (New York, N.Y.)
|November 29, 1996
Summary
Structure-activity relationship by Nuclear Magnetic Resonance (SAR by NMR) rapidly identifies and links small molecules to create high-affinity protein ligands. This method accelerates drug discovery by reducing synthesis time and chemical requirements.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Drug Discovery
Background:
- Developing high-affinity ligands is crucial for targeted drug research.
- Traditional methods for ligand discovery can be time-consuming and require extensive synthesis.
- Identifying molecules that bind to specific protein subsites presents a challenge.
Purpose of the Study:
- To introduce a novel Nuclear Magnetic Resonance (NMR)-based method for identifying, optimizing, and linking small molecules.
- To demonstrate the rapid discovery of high-affinity ligands using this new approach.
- To highlight the method's efficiency in reducing synthesis and time for drug research.
Main Methods:
- Utilizing Nuclear Magnetic Resonance (NMR) spectroscopy to analyze molecular interactions.
- Employing a "SAR by NMR" strategy to derive structure-activity relationships.
- Tethering small organic molecules that bind to proximal protein subsites.
Main Results:
- Successfully identified compounds with nanomolar affinities for the FK506 binding protein.
- Demonstrated rapid discovery of high-affinity ligands by linking micromolar affinity binders.
- Validated the "SAR by NMR" approach for efficient ligand development.
Conclusions:
- The "SAR by NMR" method significantly accelerates the discovery of high-affinity ligands.
- This technique reduces the need for extensive chemical synthesis and development time.
- The approach is particularly valuable for target-directed drug discovery and research.