Pulsed Ultrafiltration Mass Spectrometry: A New Method for Screening Combinatorial Libraries
Abstract
In response to the need for rapid screening of combinatorial libraries to identify new lead compounds during drug discovery, we have developed an on-line combination of ultrafiltration and electrospray mass spectrometry, called pulsed ultrafiltration mass spectrometry, which facilitates the identification of solution-phase ligands in library mixtures that bind to solution-phase receptors. After ligands contained in a library mixture were bound to a macromolecular receptor, e.g., human serum albumin or calf intestine adenosine deaminase, the ligand-receptor complexes were purified by ultrafiltration and then dissociated using methanol to elute the ligands into the electrospray mass spectrometer for detection. Ligands with dissociation constants in the micromolar to nanomolar range were successfully bound, released, and detected using this method, including warfarin, salicylate, furosemide, and thyroxine binding to human serum albumin, and erythro-9-(2-hydroxy-3-nonyl)adenine binding to calf intestine adenosine deaminase. Repetitive bind- and-release experiments demonstrated that the receptor could be reused. Thus, pulsed ultrafiltration mass spectrometry was shown to provide a simple and powerful new method for the screening of combinatorial libraries in support of new drug discovery.
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Native MS detects ligands directly bound to a protein, whereas affinity MS approaches typically measure ligand binding indirectly as free compounds.
“An important difference between native MS and affinity MS is that native MS detects ligands directly bound to a protein, whereas affinity MS approaches typically measure ligand binding indirectly as free compounds.”
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- Authors
- van Breemen, R. B., Huang, C.-R., Nikolic, D., Woodbury, C. P., Zhao, Y.-Z., & Venton, D. L.
- Affiliations
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, M/C 781, Chicago, Illinois 60612-7231
- University of Illinois Chicago (US)
- ORCID
- Nikolic, Dejan
- Venue
- Analytical Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1997-06-01
- Volume
- 69
- Issue
- 11
- Pages
- 2159-2164
- ISSN
- 0003-2700 (ISSN-L)
- 1520-6882
- OpenAlex
- W2092397081
- Cited by
- 167
- References
- 23
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 6 · 2023: 9 · 2022: 8 · 2021: 6 · 2020: 7 · 2019: 11 · 2018: 4 · 2017: 4 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 7 · 2012: 2
- FWCI
- 6.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Analytical Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- combinatorial library screening, ligand-receptor binding, human serum albumin, lead compound identification, drug discovery, thyroxine binding, EHNA
- MeSH terms
- Adenine, Adenosine Deaminase, Methanol, Animals, Cattle, Enzyme Inhibitors, Furosemide, Humans, Intestines, Ligands, Molecular Weight, Online Systems, Pulsatile Flow, Salicylates, Serum Albumin, Mass Spectrometry, Thyroxine, Ultrafiltration, Warfarin, Drug Design, Salicylic Acid
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