B CUBE, Center for Molecular Bioengineering, Technische Universität Dresden, Dresden, Germany.
DyNAbind GmbH, Dresden, Germany.
Nat Commun. 2023 Mar 17;14(1):1481. doi: 10.1038/s41467-023-37071-1.
The split-and-pool method has been widely used to synthesize chemical libraries of a large size for early drug discovery, albeit without the possibility of meaningful quality control. In contrast, a self-assembled DNA-encoded chemical library (DEL) allows us to construct an m x n-member library by mixing an m-member and an n-member pre-purified sub-library. Herein, we report a trio-pharmacophore DEL (T-DEL) of m x l x n members through assembling three pre-purified and validated sub-libraries. The middle sub-library is synthesized using DNA-templated synthesis with different reaction mechanisms and designed as a linkage connecting the fragments displayed on the flanking two sub-libraries. Despite assembling three fragments, the resulting compounds do not exceed the up-to-date standard of molecular weight regarding drug-likeness. We demonstrate the utility of T-DEL in linker optimization for known binding fragments against trypsin and carbonic anhydrase II and by de novo selections against matrix metalloprotease-2 and -9.
分合方法已广泛用于合成用于早期药物发现的大型化学文库，尽管无法进行有意义的质量控制。相比之下，自组装 DNA 编码化学文库 (DEL) 使我们能够通过混合一个 m 成员和一个 n 成员的预纯化子库来构建一个 m x n 成员的文库。在此，我们通过组装三个预纯化和验证过的子库报告了一个三联药效团 DEL（T-DEL）的 m x l x n 成员。中间子库是使用具有不同反应机制的 DNA 模板合成合成的，并设计为连接在两个侧翼子库上显示的片段的连接。尽管组装了三个片段，但得到的化合物的分子量并不超过目前药物相似性的标准。我们展示了 T-DEL 在连接子优化中的用途，用于针对胰蛋白酶和碳酸酐酶 II 的已知结合片段，以及针对基质金属蛋白酶-2 和 -9 的从头选择。
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