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Computer-Aided Design of Metal Ion Hosts
Benjamin P. Hay, 30 April 2003
Battelle
U.S. Department of Energy
Pacific Northwest National Laboratory
The DOE Legacy - Radioactive Waste
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Separations
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Ion exchange processes also have largescale application at DOE sites. At Hanford, tank waste pretreatment will use ion exchange to remove pertechnetate and cesium prior to vitrification.
Sensors
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Medical Applications
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Hosts for metal ions
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Host Design
Computer-Aided ?
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Architecture - scaffolds used to connect sets of binding sites
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Structural effects are often difficult to predict
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
How do we approach this problem?
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Electronic structure calculations
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Force field calculations are much, much quicker
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Downside - MM models often require parameterization
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Extending MM3 models for f-element complexes
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
What can we learn by examining host structures?
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Binding site geometry in crowns favors large metals
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Sizematch is not sufficient for a good fit
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
12-crown-4 versus 14-crown-4
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Ligand strain energy
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Binding affinity vs. host strain
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Another example
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Actinide sequestering agents
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
A closer look at the malonamide architecture
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Improved architecture?
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Proof in the pudding . . .
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Structural design criteria
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Structural design is a trialanderror process
Problem: you have to build structures before you can test them.
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
ComputerAided Host Design
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Structure-Based Drug Design
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Structure-based host design?
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
HostDesigner Software
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
LINKER algorithm
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Scoring by geometry
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Linking fragment database
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
CnHm for n = 0 - 6 (excluding alkynes, 3-membered rings, and 4-membered rings)
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Dimethylated 5 and 6membered rings
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Selected fusedrings
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Example of a LINKER run
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Validation
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
How did we do?
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Second generation
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
OVERLAY algorithm
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Tetradentate ether macrocycles
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Applications in progress
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Further information
Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
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