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Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches
Published on: October 13, 2022
Allosteric Tuning of Caspase-7: Establishing the Nexus of Structure and Catalytic Power
Kathryn F Hobbs1, Jonah Propp2, Nicholas R Vance2
1Biochemistry and Molecular Biology Department, University of Iowa, 51 Newton Road, 4-403 Bowen Science Building, Iowa City, IA, 52242, USA.
Abstract:
Caspase-7 (C7), a cysteine protease involved in apoptosis, is a valuable drug target for its role in human diseases (e. g., Parkinson's, Alzheimer's, sepsis). The C7 allosteric site has great potential for small-molecule targeting, but numerous drug discovery efforts have identified precious few allosteric inhibitors. Here we present the first selective, drug-like inhibitor of C7 along with several other improved inhibitors based on our previous fragment hit. We also provide a rational basis for the impact of allosteric binding on the C7 catalytic cycle by using an integrated approach including X-ray crystallography, stopped-flow kinetics, and molecular dynamics simulations. Our findings suggest allosteric binding disrupts C7 pre-acylation by neutralization of the catalytic dyad, displacement of substrate from the oxyanion hole, and altered dynamics of substrate binding loops. This work advances drug targeting efforts and bolsters our understanding of allosteric structure-activity relationships (ASARs).
Insights
Researchers developed the first selective, drug-like allosteric inhibitor for Caspase-7 (C7), a key protein in apoptosis and diseases like Alzheimer's. This discovery offers new therapeutic strategies by understanding how allosteric binding impacts C7's function.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- Caspase-7 (C7) is a cysteine protease crucial in apoptosis and implicated in neurodegenerative diseases and sepsis.
- The allosteric site of C7 presents a promising but underexplored target for small-molecule inhibitors.
- Previous drug discovery efforts have yielded limited success in identifying potent allosteric C7 inhibitors.
Purpose of the Study:
- To present the first selective, drug-like allosteric inhibitor for Caspase-7 (C7).
- To characterize the mechanism by which allosteric binding affects the C7 catalytic cycle.
- To advance the understanding of allosteric structure-activity relationships (ASARs) for C7.
Main Methods:
- Fragment-based drug discovery and medicinal chemistry optimization.
- X-ray crystallography to determine inhibitor-bound structures.
- Stopped-flow kinetics and molecular dynamics simulations to analyze the catalytic cycle.
Main Results:
- Identification and characterization of a novel, selective, drug-like allosteric C7 inhibitor.
- Elucidation of the allosteric inhibition mechanism, involving catalytic dyad neutralization and substrate binding disruption.
- Detailed structural and dynamic insights into the allosteric modulation of C7 activity.
Conclusions:
- The developed inhibitor represents a significant advancement in targeting C7 for therapeutic purposes.
- Allosteric inhibition of C7 disrupts key steps in its catalytic cycle, offering a new therapeutic modality.
- This study provides a foundation for future drug development targeting C7 and related proteases.
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