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首页> 外文期刊>ACS combinatorial science >DNA-Encoded Solid-Phase Synthesis: Encoding Language Design and Complex Oligomer Library Synthesis
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DNA-Encoded Solid-Phase Synthesis: Encoding Language Design and Complex Oligomer Library Synthesis

机译：DNA编码的固相合成：编码语言设计和复杂的低聚物文库合成

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摘要

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 X 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-mu m quality control beads and 10-mu 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.
机译：利用组合合成技术进​​行小分子发现的前景仍未实现，这主要归因于“结构解析问题”：后端质谱分析法，该分析法极大地限制了单珠一化合物（OBOC）库的复杂性。在大多数文库中，明显缺乏赋予结合力和特异性的分子特性，例如立体化学，区域化学和支架刚性，这是因为异构性引入了质量冗余，并且不同的支架会产生无法解释的MS片段化。在这里，我们介绍了DNA编码的固相合成（DESPS），包括在有机溶剂中的平行化合物合成以及未保护的dsDNA寡核苷酸的水性酶促连接。计算编码语言设计产生了148个热力学优化的序列，汉明字符串距离> = 3，总读取长度<100个碱基，便于测序。在6个编码位置上，连接是有效的（70％的产率），特定的方向性。一系列异构体用作DESPS拆分和合并池多样化的实用程序的试验台。单珠定量PCR检测到9 X 10（4）分子/珠，测序可阐明每种化合物的合成历史。我们将DESPS用于使用混合规模树脂（160微米质量控制珠和10微米筛选珠）的75 645人OBOC库的组合合成，该库包含支架，立体化学和区域化学多样性。对19个质控珠的串联DNA测序/ MALDI-TOF MS分析显示，DNA序列预测的质量与观察到的质量之间具有极好的一致性（<1 ppt）。 DESPS协同结合了固相合成和DNA编码的优势，从而能够使用通常被认为与未保护的DNA不相容的反应对复杂化合物进行单珠结构阐明和合成。廉价的寡核苷酸合成，酶，DNA测序和PCR的广泛普及使DESPS的实现变得简单明了，并可能促使化学界重新审视更复杂多样的文库的合成。

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