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Ligand and Target Discovery by Fragment-Based Screening in Human Cells
Open accessAbstract
Advances in the synthesis and screening of small-molecule libraries have accelerated the discovery of chemical probes for studying biological processes. Still, only a small fraction of the human proteome has chemical ligands. Here, we describe a platform that marries fragment-based ligand discovery with quantitative chemical proteomics to map thousands of reversible small molecule-protein interactions directly in human cells, many of which can be site-specifically determined. We show that fragment hits can be advanced to furnish selective ligands that affect the activity of proteins heretofore lacking chemical probes. We further combine fragment-based chemical proteomics with phenotypic screening to identify small molecules that promote adipocyte differentiation by engaging the poorly characterized membrane protein PGRMC2. Fragment-based screening in human cells thus provides an extensive proteome-wide map of protein ligandability and facilitates the coordinated discovery of bioactive small molecules and their molecular targets.
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“Equipping noncovalent fragments with a photoreactive diazirine moiety similarly enables their proteome-wide target identification without the prerequisite of a particular amino acid in or nearby a ligandable site.98−100”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [98]
In the citing paper
“We recently introduced a strategy that integrates FBLD with chemical proteomics to globally assess small molecule-protein interactions in human cells13.”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [13]
In the citing paper
“As a consequence, we found that individual FFF probes showed substantial differences in their overall proteomic interaction profiles, which made for complicated structure-activity relationships (SARs) requiring careful manual review to identify fragment-protein interactions that reflected authentic recognition events (versus simply correlating with the overall proteomic interaction profiles of the”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [13]
In the citing paper
“Moreover, while many of the enantioprobe targets were also enriched by members of the original FFF probe set13, these previous profiles often did not provide useful SAR information, either reflecting substantial enrichment by all of the FFF probes or mirroring the respective global protein interaction footprints of these probes (Supplementary Fig. 2).”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [13]
In the citing paper
“Nonetheless, we also found that individual FFFs showed substantially different overall protein interaction profiles in human cells, which complicated the assignment of small molecule-protein interactions displaying authentic SARs (vs nonspecific binding to the FFFs).”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [13]
In the citing paper
“The initial set of fully functionalized (clickable, photoreactive) fragments (FFFs) uncovered many new small molecule-protein interactions, some of which were advanced to selective and cell-active chemical probes.”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [13]
In the citing paper
“We previously described a chemical proteomic strategy to perform fragment-based ligand discovery experiments in human cells13.”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [13]
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Schonhoft, J. D., Monteiro, C., Plate, L., Eisele, Y. S., Kelly, J. W., Boland, D., Parker, C. G., Cravatt, B. F., Teruya, S. L., Helmke, S. T., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aam7621 · Cited by 71
Self-citationAn Overview of Cell-Based Assay Platforms for the Solute Carrier Family of Transporters
Dvorak, V., Wiedmer, T., Inglés‐Prieto, Á., Altermatt, P., Batoulis, H., Bärenz, F., Bender, E., Digles, D., Dürrenberger, F., Heitman, L. H., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.722889 · Cited by 72
Fragment-to-Lead Medicinal Chemistry Publications in 2017
Mortenson, P. N., Erlanson, D. A., de Esch, I. J. P., Jahnke, W., & Johnson, C. N. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01472 · Cited by 69
Approaches to target tractability assessment – a practical perspective
Brown, K. K., Hann, M. M., Lakdawala, A. S., Santos, R., Thomas, P. J., & Todd, K. (2018) · MedChemComm · doi:10.1039/c7md00633k · Cited by 69
Synthesis of portimines reveals the basis of their anti-cancer activity
Tang, J., Li, W., Chiu, T.-Y., Martínez‐Peña, F., Luo, Z., Chong, C. T., Wei, Q., Gazaniga, N. R., West, T. J., See, Y. Y., et al. (2023) · Nature · doi:10.1038/s41586-023-06535-1 · Cited by 66
Self-citationComess, K. M., McLoughlin, S. M., Oyer, J. A., Richardson, P. L., Stöckmann, H., Vasudevan, A., & Warder, S. E. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01921 · Cited by 66
New approaches to target RNA binding proteins
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Multiplexed Thiol Reactivity Profiling for Target Discovery of Electrophilic Natural Products
Tian, C., Sun, R., Liu, K., Fu, L., Liu, X., Zhou, W., Yang, Y., & Yang, J. H. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.08.022 · Cited by 62
Bioactive Compound Collections: From Design to Target Identification
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Chemoproteomic-enabled phenotypic screening
Conway, L. P., Li, W., & Parker, C. G. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.01.012 · Cited by 62
Self-citationThe era of high-quality chemical probes
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Machine learning for target discovery in drug development
Rodrigues, T., & Bernardes, G. J. L. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.10.003 · Cited by 61
Nuisance compounds in cellular assays
Dahlin, J. L., Auld, D. S., Rothenaigner, I., Haney, S., Sexton, J. Z., Nissink, J. W. M., Walsh, J. J., Lee, J. A., Strelow, J. M., Willard, F. S., et al. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.01.021 · Cited by 61
A Photoaffinity‐Based Fragment‐Screening Platform for Efficient Identification of Protein Ligands
Grant, E. K., Fallon, D. J., Hann, M. M., Fantom, K. G. M., Quinn, C. J., Zappacosta, F., Annan, R. S., Chung, C., Bamborough, P., Dixon, D. P., et al. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202008361 · Cited by 59
Novel lipid tools and probes for biological investigations
Laguerre, A., & Schultz, C. (2018) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2018.06.013 · Cited by 57
Current and promising novel drug candidates against visceral leishmaniasis
Reguera, R. M., Pérez‐Pertejo, Y., Gutiérrez-Corbo, C., Domínguez-Asenjo, B., Ordóñez, C., García‐Estrada, C., Valladares, M. M., & Balaña‐Fouce, R. (2019) · Pure and Applied Chemistry · doi:10.1515/pac-2018-1102 · Cited by 56
Towards detecting regulatory protein–metabolite interactions
Diether, M., & Sauer, U. (2017) · Current Opinion in Microbiology · doi:10.1016/j.mib.2017.07.006 · Cited by 55
Proteomics in the pharmaceutical and biotechnology industry: a look to the next decade
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Functionalized Scout Fragments for Site-Specific Covalent Ligand Discovery and Optimization
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Self-citationDecarboxylative Amination: Diazirines as Single and Double Electrophilic Nitrogen Transfer Reagents
Chandrachud, P. P., Wojtas, Ł., & Lopchuk, J. M. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c09403 · Cited by 54
Metadata
- Authors
- Parker, C. G., Galmozzi, A., Wang, Y., Correia, B. E., Sasaki, K., Joslyn, C. M., Kim, A. S., Cavallaro, C. L., Lawrence, R. M., Johnson, S. R., Narvaiza, I., Saez, E., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Bristol-Myers Squibb (United States) (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Parker, Christopher G.
- Cravatt, Benjamin F.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 168
- Issue
- 3
- Pages
- 527-541.e29
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5632530
- OpenAlex
- W2575838842
- Cited by
- 439
- References
- 59
- Citations by year
- 2026: 29 · 2025: 44 · 2024: 42 · 2023: 49 · 2022: 55 · 2021: 50 · 2020: 49 · 2019: 52 · 2018: 39 · 2017: 29
- FWCI
- 19.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- American Cancer Society (PF-14-100-01-CDD)
- American Heart Association (14POST18200019)
- NIH (DK099810, CA132630, 1S10OD16357)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- fragment screening, chemical probes, protein-ligand interactions, human proteome, target identification, PGRMC2, adipogenesis, membrane proteins, site-specific binding, phenotypic screening, ligand discovery
- MeSH terms
- Cell Differentiation, Humans, Hydrolases, Ligands, Membrane Proteins, Oxidoreductases, Protein Binding, Receptors, Progesterone, Adipocytes, Crystallography, X-Ray, Proteomics, Small Molecule Libraries, Drug Discovery, High-Throughput Screening Assays
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