title: Diversity-oriented synthetic strategy for developing a chemical modulator of protein-protein interaction.
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.
authors: Department of Biophysics and Chemical Biology, CRI Center for Chemical Proteomics, Seoul National University, Seoul 151-747, Korea.
authors: Jonghoon
authors: J
authors: Kim
authors: Department of Biophysics and Chemical Biology, CRI Center for Chemical Proteomics, Seoul National University, Seoul 151-747, Korea.
authors: Jinjoo
authors: J
authors: Jung
authors: Department of Biophysics and Chemical Biology, CRI Center for Chemical Proteomics, Seoul National University, Seoul 151-747, Korea.
authors: Jaeyoung
authors: J
authors: Koo
authors: Department of Chemistry, Seoul National University, Seoul 151-747, Korea.
authors: Wansang
authors: W
authors: Cho
authors: Department of Biophysics and Chemical Biology, CRI Center for Chemical Proteomics, Seoul National University, Seoul 151-747, Korea.
authors: Won Seok
authors: WS
authors: Lee
authors: Department of Chemistry, Seoul National University, Seoul 151-747, Korea.
authors: Chanwoo
authors: C
authors: Kim
authors: Department of Biophysics and Chemical Biology, CRI Center for Chemical Proteomics, Seoul National University, Seoul 151-747, Korea.
authors: Wonwoo
authors: W
authors: Park
authors: Department of Biophysics and Chemical Biology, CRI Center for Chemical Proteomics, Seoul National University, Seoul 151-747, Korea.|Department of Chemistry, Seoul National University, Seoul 151-747, Korea.
authors: Seung Bum
authors: 0000-0003-1753-1433
authors: SB
authors: Park
mesh_terms: D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007935:Leucine-tRNA Ligase / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects*; D011743:Pyrimidines / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011743:Pyrimidines; C430723:RRAGD protein, human; D054852:Small Molecule Libraries; D020559:Monomeric GTP-Binding Proteins; D007935:Leucine-tRNA Ligase