X‑ray Crystal Structures of Escherichia coli RNA Polymerase with Switch Region Binding Inhibitors Enable Rational Design of Squaramides with an Improved Fraction Unbound to Human Plasma Protein

Squaramides constitute a novel class of RNA polymerase inhibitors of which genetic evidence and computational modeling previously have suggested an inhibitory mechanism mediated by binding to the RNA polymerase switch region. An iterative chemistry program increased the fraction unbound to human pla...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2015-04, Vol.58 (7), p.3156-3171
Main Authors: Molodtsov, Vadim, Fleming, Paul R, Eyermann, Charles J, Ferguson, Andrew D, Foulk, Melinda A, McKinney, David C, Masse, Craig E, Buurman, Ed T, Murakami, Katsuhiko S
Format: Article
Language:English
Subjects:
Binding Sites
Blood Proteins - metabolism
Chemistry Techniques, Synthetic
Crystallography, X-Ray
DNA-Directed RNA Polymerases - antagonists & inhibitors
DNA-Directed RNA Polymerases - chemistry
DNA-Directed RNA Polymerases - metabolism
Drug Design
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Escherichia coli Proteins - antagonists & inhibitors
Escherichia coli Proteins - chemistry
Escherichia coli Proteins - genetics
Escherichia coli Proteins - metabolism
Haemophilus influenzae - drug effects
High-Throughput Screening Assays
Humans
Lactones - chemistry
Lactones - metabolism
Lactones - pharmacology
Models, Molecular
Protein Conformation
Structure-Activity Relationship
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Description
Summary:Squaramides constitute a novel class of RNA polymerase inhibitors of which genetic evidence and computational modeling previously have suggested an inhibitory mechanism mediated by binding to the RNA polymerase switch region. An iterative chemistry program increased the fraction unbound to human plasma protein from below minimum detection levels, i.e.,
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00050