Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease
| Autor: | Credille, Cy V, Dick, Benjamin L, Morrison, Christine N, Stokes, Ryjul W, Adamek, Rebecca N, Wu, Nicholas C, Wilson, Ian A, Cohen, Seth M |
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| Rok vydání: | 2018 |
| Předmět: |
Protein Conformation
Medicinal & Biomolecular Chemistry Organic Chemistry Molecular DNA-Directed RNA Polymerases Pharmacology and Pharmaceutical Sciences Endonucleases Influenza Inhibitory Concentration 50 Structure-Activity Relationship Medicinal and Biomolecular Chemistry Infectious Diseases Good Health and Well Being Metals Models Drug Discovery Influenza A Virus Pneumonia & Influenza Humans H1N1 Subtype Enzyme Inhibitors |
| Zdroj: | Journal of medicinal chemistry, vol 61, iss 22 |
| Popis: | Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure-activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PAN endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PAN endonuclease, a class of highly active and selective fragments was developed that displays IC50 values |
| Databáze: | OpenAIRE |
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