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Screening solution-phase combinatorial libraries using pulsed ultrafiltration/electrospray mass spectrometry
Y Z Zhao1, R B van Breemen, D Nikolic
1Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago 60612-7231, USA.
Journal of Medicinal Chemistry
|December 24, 1997
Summary
This study introduces a one-pot synthesis and screening method using pulsed ultrafiltration/electrospray mass spectrometry (PUF/ESMS) to rapidly identify high-affinity drug candidates. The approach successfully predicted adenosine deaminase inhibitor activity, guiding further synthesis and bioassays.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Analytical Chemistry
Background:
- Drug discovery often involves synthesizing and screening numerous compounds.
- Identifying high-affinity ligands efficiently is crucial for accelerating the drug development process.
Purpose of the Study:
- To develop and validate a rapid screening method for identifying potent drug candidates.
- To assess the utility of pulsed ultrafiltration/electrospray mass spectrometry (PUF/ESMS) in a one-pot synthesis workflow.
Main Methods:
- One-pot synthesis of adenosine deaminase inhibitor analogues (EHNA).
- Screening of crude reaction mixtures using competitive binding assay with pulsed ultrafiltration/electrospray mass spectrometry (PUF/ESMS).
- Verification of screening results through individual synthesis and bioassays.
Main Results:
- PUF/ESMS screening successfully identified active EHNA derivatives and their homologues.
- The method predicted the relative binding affinities, distinguishing active from inactive compounds.
- Bioassays confirmed the PUF/ESMS predictions for adenosine deaminase inhibition.
Conclusions:
- The described one-pot synthesis combined with PUF/ESMS screening is an effective strategy for rapid drug candidate identification.
- This method can significantly expedite the early stages of drug discovery by providing quick feedback on ligand affinity.
- PUF/ESMS offers a valuable tool for directing medicinal chemists toward promising molecular structures.