Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
Laboratory of Molecular Pharmacology & Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States.
Chemistry. 2022 Dec 20;28(71):e202201925. doi: 10.1002/chem.202201925. Epub 2022 Nov 3.
Polynucleotides, DNA and RNA (mRNA and non-coding RNAs) are critically involved in the molecular pathways of disease. Small molecule binding interactions with polynucleotides can modify functional polynucleotide topologies and/or their interactions with proteins. Current approaches to library design (lead-like or fragment-like libraries) are based on protein-ligand interactions and often include careful consideration of the 3-dimensional orientation of binding motifs and exclude π-rich compounds (polyfused aromatics) to avoid off-target R/DNA interactions. In contrast to proteins, where π,π-interactions are weak, polynucleotides can form strong π,π-interactions with suitable π-rich ligands. To assist in designing a polynucleotide-biased library, a scaffold-divergent synthesis approach to polyfused aromatic scaffolds has been undertaken. Initial screening hits that form moderately stable polynucleotide-ligand-protein ternary complexes can be further optimized through judicious incorporation of substituents on the scaffold to increase protein-ligand interactions. An example of this approach is given for topoisomerase-1 (TOP1), generating a novel TOP1 inhibitory chemotype.
多核苷酸、DNA 和 RNA（mRNA 和非编码 RNA）在疾病的分子途径中起着至关重要的作用。小分子与多核苷酸的结合相互作用可以修饰功能性多核苷酸拓扑结构和/或它们与蛋白质的相互作用。目前的文库设计方法（类先导化合物或片段样文库）基于蛋白质-配体相互作用，并且经常包括仔细考虑结合基序的三维取向，并排除富含π 的化合物（稠合芳烃）以避免非靶标 R/DNA 相互作用。与蛋白质不同，其中π,π-相互作用较弱，多核苷酸可以与合适的富含π 的配体形成强π,π-相互作用。为了协助设计偏向多核苷酸的文库，已经采用了支架发散合成方法来合成稠合芳烃支架。可以通过在支架上明智地引入取代基来进一步优化形成适度稳定的多核苷酸-配体-蛋白质三元复合物的初始筛选命中，以增加蛋白质-配体相互作用。以拓扑异构酶 1（TOP1）为例，生成了一种新型的 TOP1 抑制化学型。
