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Allosteric Tuning of Caspase-7: A Fragment-Based Drug Discovery Approach
Journal article   Open access   Peer reviewed

Allosteric Tuning of Caspase-7: A Fragment-Based Drug Discovery Approach

Nicholas R Vance, Lokesh Gakhar and M Ashley Spies
Angewandte Chemie (International ed.), Vol.56(46), pp.14443-14447
11/13/2017
DOI: 10.1002/anie.201706959
PMCID: PMC5698726
PMID: 28940929
url
https://doi.org/10.1002/anie.201706959View
Published (Version of record) Open Access

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Abstract

The caspase family of cysteine proteases are highly sought-after drug targets owing to their essential roles in apoptosis, proliferation, and inflammation pathways. High-throughput screening efforts to discover inhibitors have gained little traction. Fragment-based screening has emerged as a powerful approach for the discovery of innovative drug leads. This method has become a central facet of drug discovery campaigns in the pharmaceutical industry and academia. A fragment-based drug discovery campaign against human caspase-7 resulted in the discovery of a novel series of allosteric inhibitors. An X-ray crystal structure of caspase-7 bound to a fragment hit and a thorough kinetic characterization of a zymogenic form of the enzyme were used to investigate the allosteric mechanism of inhibition. This work further advances our understanding of the mechanisms of allosteric control of this class of pharmaceutically relevant enzymes, and provides a new path forward for drug discovery efforts.
 Apoptosis Allosteric Regulation - drug effects Caspase 7 - metabolism Surface Plasmon Resonance Isotopes - chemistry Catalytic Domain Solvents - chemistry Caspase 7 - chemistry Humans Crystallography, X-Ray Drug Discovery - methods Kinetics

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