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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Kim J,Jung J,Koo J,Cho W,Lee WS,Kim C,Park W,Park SB

doi

10.1038/ncomms13196

subject

Has Abstract

pub_date

2016-10-24 00:00:00

pages

13196

issn

2041-1723

pii

ncomms13196

journal_volume

7

pub_type

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