Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

Jonghoon Kim, Jinjoo Jung, Jaeyoung Koo, Wansang Cho, Won Seok Lee, Chanwoo Kim, Wonwoo Park and Seung Bum Park ()
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Jonghoon Kim: CRI Center for Chemical Proteomics, Seoul National University
Jinjoo Jung: CRI Center for Chemical Proteomics, Seoul National University
Jaeyoung Koo: CRI Center for Chemical Proteomics, Seoul National University
Wansang Cho: Seoul National University
Won Seok Lee: CRI Center for Chemical Proteomics, Seoul National University
Chanwoo Kim: Seoul National University
Wonwoo Park: CRI Center for Chemical Proteomics, Seoul National University
Seung Bum Park: CRI Center for Chemical Proteomics, Seoul National University

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract 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 represent a key challenge. Herein, we employ functional group-pairing strategy for the DOS of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators towards unexplored bioactive chemical space. To validate the utility of this DOS library, we identify a new small-molecule inhibitor of leucyl-tRNA synthetase–RagD protein–protein interaction, which regulates the amino acid-dependent activation of mechanistic target of rapamycin complex 1 signalling pathway. This work highlights that privileged substructure-based DOS strategy can be a powerful research tool for the construction of drug-like compounds to address challenging biological targets.

Date: 2016
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DOI: 10.1038/ncomms13196

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