Electron density guided fragment-based drug design--a lead generation example

We describe here a method using protein crystallography as the sole detection tool for fragment-based lead discovery. The methodology consists of iterative design, synthesis, and X-ray crystallographic screening of three libraries of compounds. Target-specific compound design, by way of active site...

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Bibliographic Details
Published inMethods in enzymology Vol. 493; p. 487
Main Authors Abad, Marta C, Gibbs, Alan C, Zhang, Xuqing
Format Journal Article
LanguageEnglish
Published United States 2011
Subjects
Adenosine Triphosphate - metabolism
Adenylyl Imidodiphosphate - metabolism
Catalytic Domain - drug effects
Crystallography, X-Ray
Drug Design
Drug Discovery
Drug Evaluation, Preclinical - methods
Electrons
Enzyme Inhibitors - chemistry
Fructokinases - antagonists & inhibitors
Fructokinases - chemistry
Fructose - metabolism
Hydrogen Bonding
Models, Molecular
Protein Binding
Small Molecule Libraries
Sulfates - chemistry
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Summary:We describe here a method using protein crystallography as the sole detection tool for fragment-based lead discovery. The methodology consists of iterative design, synthesis, and X-ray crystallographic screening of three libraries of compounds. Target-specific compound design, by way of active site electron density in the presence of a bound fragment hit and the intentional lack of solution activity bias form the basis of our approach. We provide an example of this alternative fragment-based drug design (FBDD) method, detailing results from a campaign using ketohexokinase to generate a unique lead series with promising drug-like properties.
ISSN:1557-7988
DOI:10.1016/B978-0-12-381274-2.00019-4