becoming power user of spark: exploring the advanced ...€¦ · becoming power user of spark:...
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Becoming power user of Spark:
Exploring the advanced experiments and enhancements
Cresset European User Group Meeting – Workshops
June 2016
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Files for this workshop
> The files used in this workshop are available for download on
request
> Please send an email to [email protected] stating the
name of the workshop
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Getting help
> Full PDF manual> Written to be useful
> Definitive descriptions of options
> Somewhat lengthy to dip into
> Support > Tell us where can improve
> Gain our input on your problem
> Cresset [email protected]
> Online meetings
> Phone
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> Increased novelty
> Find gaps in patents
> Rapid assessment of available
chemistry space
> Protect your Patents
> Scaffold hop using a db of
fragments
> Find new R groups from db of
available reagents
> New ideas
> Fragment growing
Scaffold hopping from Spark
“The best bioisostere application on the market”
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> Great results> Obvious
> Less obvious
> Completely novel
> Easy to use> Few clicks for an experiment
> Property profile not just activity> Radial plot properties
> Designed to share > Result tagging
> Get the best IP position
> Find freedom to operate even in
congested space
> Map out larger chemistry spaces –
deny freedom to competitors
> Get the best properties
> Find a back up series
> Avoid your own IP
> Generate leads from patents
> Quickly step through LO
> Avoid the ‘obvious’
> Link ideas to available reagents
Why Spark?
5
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Crystallographic water replacement – fragment-growing
Becoming a power user of Spark
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Bruton’s tyrosine kinase (Btk) inhibitors
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Replacing R-group plus crystallographic water
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Reference structure from Forge
Fragment growing experiment in Spark
Finished file: WaterReplacement_PowerUserUGM.fsp
Spark: Water replacement
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Launch Forge
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Open PDB: 4ZLZ
File / Open File
Find 4zlz.pdb and
click Open
Let Forge choose the
protonation state
Click Open
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Protein Editor: Select the 4RV ligand and HOH954
With both 4RV and HOH954
selected, click Use as Reference
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Protein Editor: Import as protein
Click Import as Protein
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Combine two references into one
4RV and HOH954
are separated
Select both
references, right-
click, choose
Combine
Selected Pair
into New
Molecule
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Reference preparation: Keep only the combined reference
Delete the
separated
references using
the right-click
drop down
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Copy the reference to the clipboard (in 3D)
Edit / Copy /
Copy 3D to copy
the reference to
the clipboard
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Launch Spark
Choose Search
for Bioisosteric
Replacements
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Paste the reference from the clipboard
Paste the
reference from
the clipboard
Next
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Select the moieties to be replaced
Select the methyl
pyridyl and water
to be replaced
Next
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Spark asks for protein structure
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Select and copy the protein from Forge
Turn OFF the
reference
structure, turn
ON the protein in
the 3D view
Edit / Copy /
Copy 3D to copy
the protein
structure to the
clipboard
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Paste the protein structure in the Spark wizard
Click Paste to
paste the protein
structure
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Protein Editor
Click Import as
Protein
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Wizard shows that protein structure has been imported
Click Next
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Field constraints
Click on the field
points
associated with
water to add
constraints
Click Finish
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Select fragment databases
Choose the
eMolecules
aromatic halide
and boronic
reagent
databases
Click Show
Options
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Size criteria tab
Turn off
Automatic
constraint of
fragment size
Click
Scoring tab
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Scoring
By default, 50%
fields / 50%
shape is used for
scoring
Click Start
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Don’t wait: WaterReplacement_PowerUserUGM.fsp
Favorites – many
motifs known in
literature
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Custom radial plot profile
Radial Plot
Properties dock,
choose Strain 1
from the drop
down list
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> Displays numerical values on the
same plot
> Preferable = plot at center
> Not preferable = plot at edge
> Linear scaling in between
> MPO score in top left corner
> How well does my molecule fit the ideal
profile
Radial Plot
If you lose your radial plot, you can retrieve it from
Windows/Docks
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Filtering: Windows/Docks/Filters
Add Filter – Fav -
True
Add Filter –
Structure –
Substructure
Excludes O=C
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Field differences
Turn ON the field
differences
Areas in the contours are
higher by 2 kcal/mol
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eMolecules reagent details
Copy and paste the Parent
Title to eMolecules to add the
reagent to your cart
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Questions welcomed
Example files available from
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