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Massively Parallel, Single-Molecule Assessment of Synthetic Fidelity and Drug-Like Properties in a DNA-Encoded Library.

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Τίτλος: Massively Parallel, Single-Molecule Assessment of Synthetic Fidelity and Drug-Like Properties in a DNA-Encoded Library.
Συγγραφείς: Koch G; Address: Department of Chemistry and Biochemistry, University of California, Santa Cruz; 1156 High Street, Santa Cruz, California95064, United States., Lawler MF; Address: Anagenex, 20 Maguire Rd Suite 302, Lexington, Massachusetts02421, United States., Murray A; Address: Department of Chemistry and Biochemistry, University of California, Santa Cruz; 1156 High Street, Santa Cruz, California95064, United States., Carlson N; Address: Anagenex, 20 Maguire Rd Suite 302, Lexington, Massachusetts02421, United States., Engstrom A; Address: Department of Chemistry and Biochemistry, University of California, Santa Cruz; 1156 High Street, Santa Cruz, California95064, United States., Zhang P; Address: Department of Chemistry and Biochemistry, University of California, Santa Cruz; 1156 High Street, Santa Cruz, California95064, United States., Steiner M; Address: Department of Chemistry and Biochemistry, University of California, Santa Cruz; 1156 High Street, Santa Cruz, California95064, United States., Avila SB; Address: Department of Chemistry and Biochemistry, University of California, Santa Cruz; 1156 High Street, Santa Cruz, California95064, United States., Cloutier-Leblanc K; Address: Anagenex, 20 Maguire Rd Suite 302, Lexington, Massachusetts02421, United States., Leelananda S; Address: Anagenex, 20 Maguire Rd Suite 302, Lexington, Massachusetts02421, United States., Grady LC; Address: Anagenex, 20 Maguire Rd Suite 302, Lexington, Massachusetts02421, United States., Taechalertpaisarn J; Address: Department of Chemistry and Biochemistry, University of California, Santa Cruz; 1156 High Street, Santa Cruz, California95064, United States., Corcoran C; Address: Department of Chemistry and Biochemistry, University of California, Santa Cruz; 1156 High Street, Santa Cruz, California95064, United States., Tilmans N; Address: Anagenex, 20 Maguire Rd Suite 302, Lexington, Massachusetts02421, United States., Lokey RS; Address: Department of Chemistry and Biochemistry, University of California, Santa Cruz; 1156 High Street, Santa Cruz, California95064, United States.
Πηγή: Journal of medicinal chemistry [J Med Chem] 2026 Aug 13; Vol. 69 (15), pp. 19390-19401.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
Imprint Name(s): Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
Ιατρικοί όροι (MeSH): DNA*/chemistry , Small Molecule Libraries*/chemistry , Gene Library*, Drug Discovery/methods ; Peptide Library ; Hydrophobic and Hydrophilic Interactions ; Chromatography, Liquid
Περίληψη: DNA-encoded libraries (DELs) are powerful drug discovery tools, enabling rapid hit generation against immobilized protein targets. However, translating these hits is often hampered by synthetic inefficiency and, for libraries of "beyond-Rule-of-5" compounds such as macrocyclic peptides, by enrichment of poorly cell-permeable members. Here we introduce LC-seq, a sequencing-based chromatographic strategy that simultaneously assesses synthetic fidelity and permeability-relevant lipophilicity for individual library members. Applying LC-seq to a proof-of-concept 120,000-member peptide library, we mapped reaction efficiency across all synthetic cycles and measured each member's lipophilicity from sequencing-count-derived retention times. We identified building-block-specific structure-reactivity trends, and the on-DNA lipophilicities of resynthesized members correlated strongly with their off-DNA lipophilicities and passive permeability in artificial membranes. This simple approach enables direct, per-member assessment of compound quality and lipophilicity, with projected scalability to libraries of millions.
(© 2026 American Chemical Society.)
Grant Information: R35GM148282 U.S. Department of Health and Human Services
Substance Nomenclature: 9007-49-2 (DNA)
0 (Peptide Library)
0 (Small Molecule Libraries)
Entry Date(s): Date Created: 20260813 Date Completed: 20260813 Latest Revision: 20260813
Update Code: 20260814
DOI: 10.1021/acs.jmedchem.6c01722
PMID: 42593909
Βάση Δεδομένων: MEDLINE
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  Data: Massively Parallel, Single-Molecule Assessment of Synthetic Fidelity and Drug-Like Properties in a DNA-Encoded Library.
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  Data: DNA-encoded libraries (DELs) are powerful drug discovery tools, enabling rapid hit generation against immobilized protein targets. However, translating these hits is often hampered by synthetic inefficiency and, for libraries of "beyond-Rule-of-5" compounds such as macrocyclic peptides, by enrichment of poorly cell-permeable members. Here we introduce LC-seq, a sequencing-based chromatographic strategy that simultaneously assesses synthetic fidelity and permeability-relevant lipophilicity for individual library members. Applying LC-seq to a proof-of-concept 120,000-member peptide library, we mapped reaction efficiency across all synthetic cycles and measured each member's lipophilicity from sequencing-count-derived retention times. We identified building-block-specific structure-reactivity trends, and the on-DNA lipophilicities of resynthesized members correlated strongly with their off-DNA lipophilicities and passive permeability in artificial membranes. This simple approach enables direct, per-member assessment of compound quality and lipophilicity, with projected scalability to libraries of millions.<br /> (© 2026 American Chemical Society.)
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