Structural characterization of new deoxycytidine kinase inhibitors rationalizes the affinity-determining moieties of the molecules
| Autor: | Arnon Lavie, Julian Nomme, Caius G. Radu, Steven T. Olson, Amanda L. Armijo, Jennifer M. Murphy, Natasha D. Sansone, Ying Su |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
deoxycytidine kinase
Models Molecular Protein Conformation Stereochemistry Biophysics Plasma protein binding Crystallography X-Ray Uridine Diphosphate Nucleoside salvage chemistry.chemical_compound nucleotide salvage pathway Protein structure Models Structural Biology inhibitors parasitic diseases Deoxycytidine Kinase Humans Protein Kinase Inhibitors chemistry.chemical_classification Crystallography biology Molecular food and beverages Active site General Medicine Deoxycytidine kinase Biological Sciences Prodrug Research Papers 3. Good health carbohydrates (lipids) Uridine diphosphate Enzyme Biochemistry chemistry 5.1 Pharmaceuticals Physical Sciences Chemical Sciences X-Ray biology.protein Development of treatments and therapeutic interventions Protein Binding |
| Zdroj: | Acta crystallographica. Section D, Biological crystallography, vol 70, iss Pt 1 |
| ISSN: | 1399-0047 |
| DOI: | 10.1107/s1399004713025030 |
| Popis: | Deoxycytidine kinase (dCK) is a key enzyme in the nucleoside salvage pathway that is also required for the activation of several anticancer and antiviral nucleoside analog prodrugs. Additionally, dCK has been implicated in immune disorders and has been found to be overexpressed in several cancers. To allow the probing and modulation of dCK activity, a new class of small-molecule inhibitors of the enzyme were developed. Here, the structural characterization of four of these inhibitors in complex with human dCK is presented. The structures reveal that the compounds occupy the nucleoside-binding site and bind to the open form of dCK. Surprisingly, a slight variation in the nature of the substituent at the 5-position of the thiazole ring governs whether the active site of the enzyme is occupied by one or two inhibitor molecules. Moreover, this substituent plays a critical role in determining the affinity, improving it from >700 to 1.5 nM in the best binder. These structures lay the groundwork for future modifications that would result in even tighter binding and the correct placement of moieties that confer favorable pharmacodynamics and pharmacokinetic properties. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text