Protein-protein interaction (PPI) plays a pivotal role in various biological systems and many complex diseases including cancer, neurodegenerative diseases, and metabolic diseases are often caused by aberrant PPIs. Given its significance in the biological systems, the identification of PPI modulators could be a starting point for drug discovery and chemical biology research. However, the high-throughput screening of conventional compound libraries hasn’t been successful, due to the different structural requirement of PPI modulators. Thus, there is a great demand in the construction of novel molecular diversity. Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. However, the design and synthesis of small-molecule libraries with improved biological relevance as well as maximized molecular diversity represents a key challenge. Herein, we employ functional group pairing strategy for the diversity-oriented synthesis of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators toward unexplored bioactive chemical space. This presentation highlights that privileged substructure-based DOS (pDOS) strategy can be a powerful research tool for the construction of drug-like compounds to address challenging biological targets.
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