Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Usanov, DL, Chan, AI, Maianti, JPablo, Liu, DR |
Journal | Nat Chem |
Volume | 10 |
Issue | 7 |
Pages | 704-714 |
Date Published | 2018 07 |
ISSN | 1755-4349 |
Keywords | Codon, DNA, Macrocyclic Compounds, Small Molecule Libraries, Stereoisomerism, Templates, Genetic |
Abstract | DNA-encoded libraries have emerged as a widely used resource for the discovery of bioactive small molecules, and offer substantial advantages compared with conventional small-molecule libraries. Here, we have developed and streamlined multiple fundamental aspects of DNA-encoded and DNA-templated library synthesis methodology, including computational identification and experimental validation of a 20 × 20 × 20 × 80 set of orthogonal codons, chemical and computational tools for enhancing the structural diversity and drug-likeness of library members, a highly efficient polymerase-mediated template library assembly strategy, and library isolation and purification methods. We have integrated these improved methods to produce a second-generation DNA-templated library of 256,000 small-molecule macrocycles with improved drug-like physical properties. In vitro selection of this library for insulin-degrading enzyme affinity resulted in novel insulin-degrading enzyme inhibitors, including one of unusual potency and novel macrocycle stereochemistry (IC = 40 nM). Collectively, these developments enable DNA-templated small-molecule libraries to serve as more powerful, accessible, streamlined and cost-effective tools for bioactive small-molecule discovery. |
DOI | 10.1038/s41557-018-0033-8 |
Pubmed | |
Alternate Journal | Nat Chem |
PubMed ID | 29610462 |
PubMed Central ID | PMC6014893 |
Grant List | / / Howard Hughes Medical Institute / United States R35 GM118062 / GM / NIGMS NIH HHS / United States |
Nat Chem DOI:10.1038/s41557-018-0033-8
Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules.
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