Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify ligands for biological targets given that it enables the target to direct the synthesis and amplification of its strongest binder(s) from the library of interconverting compounds. Since the first report of DCC applied to the discovery of binders for a protein, this elegant tool has been employed on a range of protein targets at various stages of medicinal-chemistry projects. A series of suitable, reversible reactions that are biocompatible have been established and the portfolio of analytical techniques is growing. Despite progress, in most cases, the libraries employed remain of moderate size. We present here the most recent advances in the field of DCC applied to protein targets, paying particular attention to the experimental conditions and analytical methods chosen.
Structure-based design (SBD) can be used for the design and/or optimization of new inhibitors for a biological target. Whereas de novo SBD is rarely used, most reports on SBD are dealing with the optimization of an initial hit. Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify bioactive ligands given that it enables the target to direct the synthesis of its strongest binder. We have designed a library of potential inhibitors (acylhydrazones) generated from five aldehydes and five hydrazides and used DCC to identify the best binder(s). After addition of the aspartic protease endothiapepsin, we characterized the protein-bound library member(s) by saturation-transfer difference NMR spectroscopy. Cocrystallization experiments validated the predicted binding mode of the two most potent inhibitors, thus demonstrating that the combination of de novo SBD and DCC constitutes an efficient starting point for hit identification and optimization.
Ubiquitin carboxy-terminal hydrolase
L1 (UCHL1) is a deubiquitylating
enzyme that is proposed as a potential therapeutic target in neurodegeneration,
cancer, and liver and lung fibrosis. Herein we report the discovery
of the most potent and selective UCHL1 probe (IMP-1710) to date based
on a covalent inhibitor scaffold and apply this probe to identify
and quantify target proteins in intact human cells. IMP-1710 stereoselectively
labels the catalytic cysteine of UCHL1 at low nanomolar concentration
in cells. We further demonstrate that potent and selective UCHL1 inhibitors
block pro-fibrotic responses in a cellular model of idiopathic pulmonary
fibrosis, supporting the potential of UCHL1 as a potential therapeutic
target in fibrotic diseases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.