Tailoring Small Molecules for an Allosteric Site on Procaspase-6
| Autor: | Micah Steffek, Frederick Cohen, Christine Pozniak, Preeti Chugha, Joe Lewcock, Brandon J. Bravo, Yinyan Tang, Adam R. Renslo, Xianrui Zhao, Brian R. Hearn, Jeremy Murray, Michelle R. Arkin, John A. Flygare, Priyadarshini Jaishankar, Christine Tam, Cuong Ly, Paul Gibbons, Anthony M. Giannetti |
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| Rok vydání: | 2013 |
| Předmět: |
Stereochemistry
Dimer Allosteric regulation Caspase 6 Crystallography X-Ray Biochemistry Small Molecule Libraries chemistry.chemical_compound Zymogen Drug Discovery Transition Temperature General Pharmacology Toxicology and Pharmaceutics Surface plasmon resonance Caspase Pharmacology Enzyme Precursors Binding Sites biology Organic Chemistry Active site Hydrogen-Ion Concentration Small molecule Protein Structure Tertiary Molecular Docking Simulation chemistry Drug Design biology.protein Biophysics Molecular Medicine Dimerization Allosteric Site Protein Binding |
| Zdroj: | ChemMedChem. 9:73-77 |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201300424 |
| Popis: | Although they represent attractive therapeutic targets, caspases have so far proven recalcitrant to the development of drugs targeting the active site. Allosteric modulation of caspase activity is an alternate strategy that potentially avoids the need for anionic and electrophilic functionality present in most active-site inhibitors. Caspase-6 has been implicated in neurodegenerative disease, including Huntington's and Alzheimer's diseases. Herein we describe a fragment-based lead discovery effort focused on caspase-6 in its active and zymogen forms. Fragments were identified for procaspase-6 using surface plasmon resonance methods and subsequently shown by X-ray crystallography to bind a putative allosteric site at the dimer interface. A fragment-merging strategy was employed to produce nanomolar-affinity ligands that contact residues in the L2 loop at the dimer interface, significantly stabilizing procaspase-6. Because rearrangement of the L2 loop is required for caspase-6 activation, our results suggest a strategy for the allosteric control of caspase activation with drug-like small molecules. |
| Databáze: | OpenAIRE |
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