Affinity Selection and Mass Spectrometry-Based Strategies to Identify Lead Compounds in Combinatorial Libraries
Abstract
The screening of diverse libraries of small molecules created by combinatorial synthetic methods is a recent development which has the potential to accelerate the identification of lead compounds in drug discovery. We have developed a direct and rapid method to identify lead compounds in libraries involving affinity selection and mass spectrometry. In our strategy, the receptor or target molecule of interest is used to isolate the active components from the library physically, followed by direct structural identification of the active compounds bound to the target molecule by mass spectrometry. In a drug design strategy, structurally diverse libraries can be used for the initial identification of lead compounds. Once lead compounds have been identified, libraries containing compounds chemically similar to the lead compound can be generated and used to optimize the binding characteristics. These strategies have also been adopted for more detailed studies of protein-ligand interactions.
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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.”
From Native metabolomics identifies the rivulariapeptolide family of protease inhibitors (2022) · cites this paper as [25]
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BindingDB (2012) · UC San Diego · doi:10.7270/q22z167w
BindingDB Entry 1965: Affinity-based ranking of ligands for DPP-4 from mixtures
BindingDB (2007) · UC San Diego · doi:10.7270/q2m906wf
- Authors
- Kaur, S., McGuire, L., Tang, D., Dollinger, G., & Huebner, V.
- Affiliations
- Biochimie des Protéines Membranaires (FR)
- Venue
- Journal of Protein Chemistry
- Published
- 1997-07
- Volume
- 16
- Issue
- 5
- Pages
- 505-511
- ISSN
- 0277-8033 (ISSN-L)
- 1573-4943
- OpenAlex
- W1226074361
- Cited by
- 95
- References
- 15
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 2 · 2017: 1 · 2016: 2 · 2014: 1 · 2013: 2
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Protein Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- affinity selection, combinatorial libraries, lead compound identification, small molecule library, protein-ligand interactions, receptor binding, drug discovery, library optimization
- MeSH terms
- Binding, Competitive, Chromatography, Affinity, Drug Evaluation, Preclinical, Ligands, Proteins, Receptors, Drug, Mass Spectrometry, Structure-Activity Relationship, Drug Design, Peptide Library
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