Dataset Information

DNA-Encoded Solid-Phase Synthesis: Encoding Language Design and Complex Oligomer Library Synthesis.

ABSTRACT: The promise of exploiting combinatorial synthesis for small molecule discovery remains unfulfilled due primarily to the "structure elucidation problem": the back-end mass spectrometric analysis that significantly restricts one-bead-one-compound (OBOC) library complexity. The very molecular features that confer binding potency and specificity, such as stereochemistry, regiochemistry, and scaffold rigidity, are conspicuously absent from most libraries because isomerism introduces mass redundancy and diverse scaffolds yield uninterpretable MS fragmentation. Here we present DNA-encoded solid-phase synthesis (DESPS), comprising parallel compound synthesis in organic solvent and aqueous enzymatic ligation of unprotected encoding dsDNA oligonucleotides. Computational encoding language design yielded 148 thermodynamically optimized sequences with Hamming string distance ? 3 and total read length <100 bases for facile sequencing. Ligation is efficient (70% yield), specific, and directional over 6 encoding positions. A series of isomers served as a testbed for DESPS's utility in split-and-pool diversification. Single-bead quantitative PCR detected 9 × 10(4) molecules/bead and sequencing allowed for elucidation of each compound's synthetic history. We applied DESPS to the combinatorial synthesis of a 75,645-member OBOC library containing scaffold, stereochemical and regiochemical diversity using mixed-scale resin (160-?m quality control beads and 10-?m screening beads). Tandem DNA sequencing/MALDI-TOF MS analysis of 19 quality control beads showed excellent agreement (<1 ppt) between DNA sequence-predicted mass and the observed mass. DESPS synergistically unites the advantages of solid-phase synthesis and DNA encoding, enabling single-bead structural elucidation of complex compounds and synthesis using reactions normally considered incompatible with unprotected DNA. The widespread availability of inexpensive oligonucleotide synthesis, enzymes, DNA sequencing, and PCR make implementation of DESPS straightforward, and may prompt the chemistry community to revisit the synthesis of more complex and diverse libraries.

SUBMITTER: MacConnell AB

PROVIDER: S-EPMC4571006 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other

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DNA-Encoded Solid-Phase Synthesis: Encoding Language Design and Complex Oligomer Library Synthesis.

MacConnell Andrew B AB McEnaney Patrick J PJ Cavett Valerie J VJ Paegel Brian M BM

ACS combinatorial science 20150905 9

The promise of exploiting combinatorial synthesis for small molecule discovery remains unfulfilled due primarily to the "structure elucidation problem": the back-end mass spectrometric analysis that significantly restricts one-bead-one-compound (OBOC) library complexity. The very molecular features that confer binding potency and specificity, such as stereochemistry, regiochemistry, and scaffold rigidity, are conspicuously absent from most libraries because isomerism introduces mass redundancy a ...[more]

PMID: 26290177

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Project description:ImportanceCase reports that externalize expert diagnostic reasoning are utilized for clinical reasoning instruction but are difficult to search based on symptoms, final diagnosis, or differential diagnosis construction. Computational approaches that uncover how experienced diagnosticians analyze the medical information in a case as they formulate a differential diagnosis can guide educational uses of case reports.ObjectiveTo develop a "reasoning-encoded" case database for advanced clinical reasoning instruction by applying natural language processing (NLP), a sub-field of artificial intelligence, to a large case report library.DesignWe collected 2525 cases from the New England Journal of Medicine (NEJM) Clinical Pathological Conference (CPC) from 1965 to 2020 and used NLP to analyze the medical terminology in each case to derive unbiased (not prespecified) categories of analysis used by the clinical discussant. We then analyzed and mapped the degree of category overlap between cases.ResultsOur NLP algorithms identified clinically relevant categories that reflected the relationships between medical terms (which included symptoms, signs, test results, pathophysiology, and diagnoses). NLP extracted 43,291 symptoms across 2525 cases and physician-annotated 6532 diagnoses (both primary and related diagnoses). Our unsupervised learning computational approach identified 12 categories of medical terms that characterized the differential diagnosis discussions within individual cases. We used these categories to derive a measure of differential diagnosis similarity between cases and developed a website ( universeofcpc.com ) to allow visualization and exploration of 55 years of NEJM CPC case series.ConclusionsApplying NLP to curated instances of diagnostic reasoning can provide insight into how expert clinicians correlate and coordinate disease categories and processes when creating a differential diagnosis. Our reasoning-encoded CPC case database can be used by clinician-educators to design a case-based curriculum and by physicians to direct their lifelong learning efforts.

Dataset Information

DNA-Encoded Solid-Phase Synthesis: Encoding Language Design and Complex Oligomer Library Synthesis.

Publications

DNA-Encoded Solid-Phase Synthesis: Encoding Language Design and Complex Oligomer Library Synthesis.

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