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 enables their proteome-wide target identification without prerequisite of a particular amino acid in or nearby a ligandable site.
“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]
The authors previously introduced a strategy that integrates FBLD with chemical proteomics to globally assess small molecule-protein interactions in human cells.
“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]
Individual FFF probes in the authors' initial studies showed substantial differences in their overall proteomic interaction profiles, which made for complicated structure-activity relationships requiring careful manual review to identify authentic fragment-protein interactions.
“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]
While many enantioprobe targets were also enriched by members of the original FFF probe set, these previous profiles often did not provide useful SAR information.
“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]
Individual FFFs showed substantially different overall protein interaction profiles in human cells, which complicated the assignment of small molecule-protein interactions displaying authentic SARs versus nonspecific binding to the FFFs.
“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]
The initial set of fully functionalized fragments uncovered many new small molecule-protein interactions, some of which were advanced to selective and cell-active chemical probes.
“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]
We previously described a chemical proteomic strategy to perform fragment-based ligand discovery experiments in human cells.
“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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Chemoproteomics and Chemical Probes for Target Discovery
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A road map for prioritizing warheads for cysteine targeting covalent inhibitors
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Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures
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In-Cell Structural Biology by NMR: The Benefits of the Atomic Scale
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Self-citationTargeted protein acetylation in cells using heterobifunctional molecules
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The Druggability of Solute Carriers
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Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery
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Liganding Functional Tyrosine Sites on Proteins Using Sulfur–Triazole Exchange Chemistry
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Covalent fragment libraries in drug discovery
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Photoaffinity labelling strategies for mapping the small molecule–protein interactome
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A general fragment-based approach to identify and optimize bioactive ligands targeting RNA
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Self-citationEmerging targetome and signalome landscape of gut microbial metabolites
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Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry
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Proteome-scale discovery of protein degradation and stabilization effectors
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Covalent Small Molecules as Enabling Platforms for Drug Discovery
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Large-scale chemoproteomics expedites ligand discovery and predicts ligand behavior in cells
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A direct-to-biology high-throughput chemistry approach to reactive fragment screening
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Modeling covalent-modifier drugs.
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Biomolecular condensates: new opportunities for drug discovery and RNA therapeutics
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Ligand discovery by activity-based protein profiling
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Self-citationCRISPR Approaches to Small Molecule Target Identification
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Proteomic discovery of chemical probes that perturb protein complexes in human cells
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Stereochemical diversity as a source of discovery in chemical biology
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Self-citationTargeting chromatin complexes in fusion protein-driven malignancies
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Privileged Electrophile Sensors: A Resource for Covalent Drug Development
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Design, Optimization, and Study of Small Molecules That Target Tau Pre-mRNA and Affect Splicing
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Evaluation of fully-functionalized diazirine tags for chemical proteomic applications
Conway, L. P., Jadhav, A. M., Homan, R. A., Li, W., Rubiano, J. S., Hawkins, R., Lawrence, R. M., & Parker, C. G. (2021) · Chemical Science · doi:10.1039/d1sc01360b · Cited by 80 · see citing works
Self-citationFragment-to-Lead Medicinal Chemistry Publications in 2018
Erlanson, D. A., de Esch, I. J. P., Jahnke, W., Johnson, C. N., & Mortenson, P. N. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01581 · Cited by 77 · see citing works
Schreiber, S. L. (2018) · Israel Journal of Chemistry · doi:10.1002/ijch.201800113 · Cited by 76 · see citing works
Proteomics in Drug Development: The Dawn of a New Era?
Frantzi, M., Latosińska, A., & Mischak, H. (2019) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.201800087 · Cited by 75 · see citing works
Designing Chimeric Molecules for Drug Discovery by Leveraging Chemical Biology
Borsari, C., Trader, D. J., Tait, A., & Costi, M. P. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01456 · Cited by 75 · see citing works
Parker, C. G., Kuttruff, C. A., Galmozzi, A., Jørgensen, L., Yeh, C., Hermanson, D. J., Wang, Y., Artola, M., McKerrall, S. J., Josyln, C. M., et al. (2017) · ACS Central Science · doi:10.1021/acscentsci.7b00420 · Cited by 74 · see citing works
Self-citationHydrophobic Pockets of HPMC Enable Extremely Short Reaction Times in Water
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Zhang, J., Culp, M. L., Craver, J., & Darley-Usmar, V. M. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14308 · Cited by 73 · see citing works
Favalli, N., Bassi, G., Pellegrino, C. E., Millul, J., Luca, R. D., Cazzamalli, S., Yang, S., Trenner, A., Mozaffari, N. L., Myburgh, R., et al. (2021) · Nature Chemistry · doi:10.1038/s41557-021-00660-y · Cited by 72 · see citing works
Tong, Y., Gibaut, Q. M. R., Rouse, W. B., Childs‐Disney, J. L., Suresh, B. M., Abegg, D., Choudhary, S., Akahori, Y., Adibekian, A., Moss, W. N., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c01929 · Cited by 71 · see citing works
Pan, S., Ding, A., Li, Y., Sun, Y., Zhan, Y., Ye, Z., Song, N., Peng, B., Li, L., Huang, W., et al. (2023) · Chemical Society Reviews · doi:10.1039/d3cs00056g · Cited by 71 · see citing works
Targeted Covalent Modification Strategies for Drugging the Undruggable Targets
Tamura, T., Kawano, M., & Hamachi, I. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00745 · Cited by 71 · see citing works
Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients
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 · see citing works
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 69 · see citing works
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 · see citing works
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 68 · see citing works
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 · see citing works
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 · see citing works
New approaches to target RNA binding proteins
Julio, A. R., & Backus, K. M. (2021) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2020.12.006 · Cited by 65 · see citing works
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 · see citing works
Bioactive Compound Collections: From Design to Target Identification
Laraia, L., Robke, L., & Waldmann, H. (2018) · Chem · doi:10.1016/j.chempr.2018.01.012 · Cited by 61 · see citing works
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 60 · see citing works
Self-citationThe era of high-quality chemical probes
Licciardello, M. P., & Workman, P. (2022) · RSC Medicinal Chemistry · doi:10.1039/d2md00291d · Cited by 60 · see citing works
Machine learning for target discovery in drug development
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Nuisance compounds in cellular assays
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A Photoaffinity‐Based Fragment‐Screening Platform for Efficient Identification of Protein Ligands
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Novel lipid tools and probes for biological investigations
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Current and promising novel drug candidates against visceral leishmaniasis
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Towards detecting regulatory protein–metabolite interactions
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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
Crowley, V. M., Thielert, M., & Cravatt, B. F. (2021) · ACS Central Science · doi:10.1021/acscentsci.0c01336 · Cited by 53 · see citing works
Self-citationDecarboxylative Amination: Diazirines as Single and Double Electrophilic Nitrogen Transfer Reagents
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- 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
- Physical Sciences › Computer Science › Computational Theory and Mathematics › 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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