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

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Encoded combinatorial chemistry.

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

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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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Construction of Isoquinolone Scaffolds on DNA via Rhodium(III)-Catalyzed C–H Activation
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A DNA-encoded library for the identification of natural product binders that modulate poly (ADP-ribose) polymerase 1, a validated anti-cancer target
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Self-citation
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“Brenner and Lerner proposed the use of DNA for tagging chemical compounds with specific labels [Brenner and Lerner, 1992] for use in combinatorial chemistry.”
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Evaluation of DNA encoded library and machine learning model combinations for hit discovery
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Inhibitory antibodies identify unique sites of therapeutic vulnerability in rhinovirus and other enteroviruses
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“On the other, high-throughput fragment-based approaches for small molecule discovery could be considered, such as the tethering (43) and the DNA-encoded library (DEL) methods (44).”
Self-citation
Discovery of TIGIT inhibitors based on DEL and machine learning
Xiong, F., Yu, M., Xu, H., Zhong, Z., Li, Z., Guo, Y., Zhang, T., Zeng, Z., Jin, F., & He, X. (2022) · Frontiers in Chemistry · doi:10.3389/fchem.2022.982539 · Cited by 15
“…improve the success rate of new drug development is applying new technologies for hit discovery and optimization, such as DNA-encoded library (DEL) (Brenner and Lerner, 1992; Franzini et al., 2014; Johnson, 2018) and arti ﬁ cial intelligence (AI) (Smalley, 2017) et al. Thanks to the rapid growth…”
Impact of organic chemistry conditions on DNA durability in the context of DNA-encoded library technology
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“Sydney Brenner.(6) DEL is a cost-effective alternative technology compared to traditional HTS and fragment-based drug discovery.”
Background
Diversity-oriented synthesis encoded by deoxyoligonucleotides
Hudson, L., Mason, J. W., Westphal, M. V., Richter, M. J. R., Thielman, J. R., Hua, B. K., Gerry, C. J., Xia, G., Osswald, H. L., Knapp, J. M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40575-5 · Cited by 15
“…of DEL technology — to prepare large libraries of compounds through combinatorial split-and-pool chemistry with concurrent encoding of each individual molecule by a unique DNA barcode — facilitates the simul-taneousparallelscreeningofentirelibrariesofcompoundsforbinding to a target of interest 22 .”
Precision Oncology Comes of Age: Designing Best-in-Class Small Molecules by Integrating Two Decades of Advances in Chemistry, Target Biology, and Data Science
Stuart, D. D., Guzman-Perez, A., Brooijmans, N., Jackson, E. L., Kryukov, G. V., Friedman, A. A., & Hoos, A. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0280 · Cited by 19
“DNA-encoded libraries (DEL), first described conceptually in 1992 (95), have become a valuable method of identifying binding hits for challenging targets, and there are now at least three compounds in clinical development targeting sEH, RIP1, and ATX that originated from DEL hits, although these are all being develope…”
Background
Methodology of drug screening and target identification for new necroptosis inhibitors
Pan, P., Cai, Z., Zhuang, C., Chen, X., & Chai, Y. (2018) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2018.11.002 · Cited by 16
“This concept was first proposed by Brenner and Lerner in 1992 [58], then Nielsen et al.”

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: Physical Sciences › Chemistry › Organic Chemistry › 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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