Encoded combinatorial chemistry.

Brenner, S; Lerner, R A

doi:10.1073/pnas.89.12.5381

Cited by 1,014Chemical Synthesis and AnalysisDNA and Nucleic Acid ChemistryClick Chemistry and Applications

Encoded combinatorial chemistry.

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Brenner, S, Lerner, R A·1992·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.89.12.5381PMC PMC49295

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Abstract

The diversity of chemical synthesis and the power of genetics are linked to provide a powerful, versatile method for drug screening. A process of alternating parallel combinatorial synthesis is used to encode individual members of a large library of chemicals with unique nucleotide sequences. After the chemical entity is bound to a target, the genetic tag can be amplified by replication and utilized for enrichment of the bound molecules by serial hybridization to a subset of the library. The nature of the chemical structure bound to the receptor is decoded by sequencing the nucleotide tag.

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DELs are built through iterative chemical synthesis in which each small molecule is covalently linked to a unique DNA tag that enables parallel screening of millions of pooled compounds.
“Originally conceived by Brenner and lerner, Dels are built through iterative chemical synthesis in which each small molecule is covalently linked to a unique DNA tag that enables the parallel screening of millions of pooled compounds (Brenner and lerner 1992).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Brenner and lerner 1992
The paper’s description of encoded combinatorial chemistry describes alternating synthesis, chemical linkage to a unique nucleotide tag, and pooling and screening of the resulting library. But the Implementation section calls libraries of up to 10⁴ compounds reasonable under its example conditions; it does not support the claim that this method enables screening of millions of pooled compounds. (LLM, conf=0.90)
Experimental — accuracy not yet measured
DNA encoded libraries (DELs) are increasingly being adopted in drug discovery.
“Conceptualized by Brenner and Lerner, 170 DNA encoded libraries (DELs) are increasingly being adopted in drug discovery.”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [170]

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DNA Display II. Genetic Manipulation of Combinatorial Chemistry Libraries for Small-Molecule Evolution
Halpin, D. R., & Harbury, P. B. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020174 · Cited by 125 · see citing works
“DNA has been utilized previously to record the synthetic history of individual beads in a split-and-pool combinatorial synthesis, but the DNA tags could not direct subsequent resynthesis of the corresponding compound (Brenner and Lerner 1992).”
Method
A one-bead, one-stock solution approach to chemical genetics: part 1
Blackwell, H. E., Pérez, L., Stavenger, R. A., Tallarico, J. A., Cope-Eatough, E. K., Foley, M. A., & Schreiber, S. L. (2001) · Chemistry & Biology · doi:10.1016/s1074-5521(01)00085-0 · Cited by 125 · see citing works
“While numerous encoding techniques have been reported [28], including spatial [30], chemical [21,22,31,32], spectrometric”
Background
DNA-encoded chemical libraries: foundations and applications in lead discovery
Zimmermann, G., & Neri, D. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.07.013 · Cited by 124 · see citing works
“[3–5] The concept of DNA-encoded chemical libraries was first introduced by Brenner and Lerner, who postulated that it should be possible to simultaneously synthesize peptides and DNA-tags on beads, thus generating collections of encoded compounds.[6] Subsequently, it was shown that encoded chemical libraries could be…”
Background
Selection of DNA-Encoded Libraries to Protein Targets within and on Living Cells
Cai, B., Kim, D., Akhand, S. S., Sun, Y., Cassell, R. J., Alpsoy, A., Dykhuizen, E. C., van Rijn, R. M., Wendt, M. K., & Krusemark, C. J. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b08085 · Cited by 123 · see citing works
Strategies for developing DNA-encoded libraries beyond binding assays
Huang, Y., Li, Y., & Li, X. (2022) · Nature Chemistry · doi:10.1038/s41557-021-00877-x · Cited by 120 · see citing works
DNA Display III. Solid-Phase Organic Synthesis on Unprotected DNA
Halpin, D. R., Lee, J. A., Wrenn, S. J., & Harbury, P. B. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020175 · Cited by 122 · see citing works
“Given the instability of DNA in strong acids, it was necessary to identify (A) Peptide synthesis is carried out on DNA modified with a 59 C12 amino (NC20) or a 59 PEG amino (NP20) linker.”
Background
Selection of DNA‐Encoded Small Molecule Libraries Against Unmodified and Non‐Immobilized Protein Targets
Zhao, P., Chen, Z., Li, Y., Sun, D., Gao, Y., Huang, Y., & Li, X. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201404830 · Cited by 121 · see citing works
Clip Chemistry: Diverse (Bio)(macro)molecular and Material Function through Breaking Covalent Bonds
Shieh, P., Hill, M. R., Zhang, W., Kristufek, S. L., & Johnson, J. A. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01282 · Cited by 119 · see citing works
DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions
Xu, H., Ma, F., Wang, N., Hou, W., Xiong, H., Lu, F., Li, J., Wang, S., Ma, P., Yang, G., et al. (2019) · Advanced Science · doi:10.1002/advs.201901551 · Cited by 120 · see citing works
Self-citation
The rise, fall and reinvention of combinatorial chemistry
Kodadek, T. J. (2011) · Chemical Communications · doi:10.1039/c1cc12102b · Cited by 116 · see citing works
DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules
Gerry, C. J., Wawer, M. J., Clemons, P. A., & Schreiber, S. L. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b01203 · Cited by 116 · see citing works
“DELs comprise small molecules that are covalently linked to unique DNA sequences that encode, most frequently, their synthetic histories.(2,3) Large collections of DNA-barcoded compounds can be screened in a single experiment by incubating them with an immobilized macromolecular target, washing away nonbinders, and se…”
Background
The generation of molecular diversity
Pavia, M. R., Sawyer, T. K., & Moos, W. H. (1993) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(01)80220-1 · Cited by 115 · see citing works
Robust Suzuki–Miyaura Cross-Coupling on DNA-Linked Substrates
Ding, Y., & Clark, M. (2014) · ACS Combinatorial Science · doi:10.1021/co5001037 · Cited by 114 · see citing works
DNA-encoded libraries (DELs): a review of on-DNA chemistries and their output
Shi, Y., Wu, Y., Yu, J., Zhang, W., & Zhuang, C. (2021) · RSC Advances · doi:10.1039/d0ra09889b · Cited by 114 · see citing works
Molecular glues and bifunctional compounds: Therapeutic modalities based on induced proximity
Schreiber, S. L. (2024) · Cell Chemical Biology · doi:10.1016/j.chembiol.2024.05.004 · Cited by 112 · see citing works
Combinatorial approaches to materials discovery
McFarland, E. W., & Weinberg, W. H. (1999) · Trends in biotechnology · doi:10.1016/s0167-7799(98)01275-x · Cited by 111 · see citing works
Chemical Biology Probes from Advanced DNA-encoded Libraries
Salamon, H., Škopić, M. K., Jung, K., Bugain, O., & Brunschweiger, A. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.5b00981 · Cited by 110 · see citing works
DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery
Zhou, Y., Li, C., Peng, J., Xie, L., Meng, L. H., Li, Q., Zhang, J., Li, X., Li, X., Huang, X., et al. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b09277 · Cited by 110 · see citing works
Plasma induced long-term growth enhancement of Raphanus sativus L. using combinatorial atmospheric air dielectric barrier discharge plasmas
Kitazaki, S., Sarinont, T., Koga, K., Hayashi, N., & Shiratani, M. (2014) · Current Applied Physics · doi:10.1016/j.cap.2013.11.056 · Cited by 109 · see citing works
Chemical Strategies for the Synthesis of Peptide−Oligonucleotide Conjugates
Lü, K., Duan, Q., Ma, L., & Zhao, D. (2009) · Bioconjugate Chemistry · doi:10.1021/bc900158s · Cited by 109 · see citing works
Discovery of TNF Inhibitors from a DNA-Encoded Chemical Library based on Diels-Alder Cycloaddition
Buller, F., Zhang, Y., Scheuermann, J., Schäfer, J., Bühlmann, P., & Neri, D. (2009) · Chemistry & Biology · doi:10.1016/j.chembiol.2009.09.011 · Cited by 109 · see citing works
A one-bead, one-stock solution approach to chemical genetics: part 2
Clemons, P. A., Koehler, A. N., Wagner, B. K., Sprigings, T. G., Spring, D. R., King, R. W., Schreiber, S. L., & Foley, M. A. (2001) · Chemistry & Biology · doi:10.1016/s1074-5521(01)00086-2 · Cited by 107 · see citing works
“While numerous encoding techniques have been reported [28], including spatial [30], chemical [21,22, 31 ,32], spectrometric”
Background
Recent achievements and current trajectories of diversity-oriented synthesis
Gerry, C. J., & Schreiber, S. L. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.08.008 · Cited by 106 · see citing works
Large-Pore Mesoporous Materials with Semi-Crystalline Zeolitic Frameworks
On, D. T., & Kaliaguine, S. (2001) · Angewandte Chemie International Edition · doi:10.1002/1521-3773(20010903)40:17 · Cited by 224 · see citing works
Employing Photoredox Catalysis for DNA‐Encoded Chemistry: Decarboxylative Alkylation of α‐Amino Acids
Kölmel, D. K., Loach, R. P., Knauber, T., & Flanagan, M. E. (2018) · ChemMedChem · doi:10.1002/cmdc.201800492 · Cited by 105 · see citing works
Mycobacterium enoyl acyl carrier protein reductase (InhA): A key target for antitubercular drug discovery
Prasad, M. S., Bhole, R. P., Khedekar, P. B., & Chikhale, R. V. (2021) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2021.105242 · Cited by 106 · see citing works

Solid-phase combinatorial chemistry and novel tagging methods for identifying leads
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DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information
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Self-citation
DNA ‐encoded chemical libraries – achievements and remaining challenges
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[16] Encoded combinatorial chemistry: Binary coding using chemically robust secondary amine tags
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Combinatorial technology revitalized by DNA‐encoding
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Authors: Brenner, S., & Lerner, R. A.
Affiliations: Scripps Research Institute (US)
ORCID: Lerner, R A
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1992-06-15
Volume: 89
Issue: 12
Pages: 5381-5383
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.89.12.5381
PMC: PMC49295
OpenAlex: W2017423606
Cited by: 1,014
References: 9
Citations by year: 2026: 60 · 2025: 77 · 2024: 71 · 2023: 73 · 2022: 87 · 2021: 72 · 2020: 52 · 2019: 55 · 2018: 30 · 2017: 32 · 2016: 25 · 2015: 24 · 2014: 13 · 2013: 9 · 2012: 8
FWCI: 8.46
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
Keywords: drug screening, gene tagging, ligand-receptor binding
MeSH terms: Amino Acid Sequence, Base Sequence, Molecular Sequence Data, Peptides, Restriction Mapping, Drug Design, Polymerase Chain Reaction, Databases, Factual

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