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Introduction to Spark: Discover new directions for your project using bioisosteres Cresset European User Group Meeting – Workshops June 2016
Introduction to Spark:
Discover new directions for your project using bioisosteres
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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Cresset technology and scientific approach
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Field points
3D Molecular Electrostatic
Interaction Potential (MIP)
Field Points
= Positive = Negative
= Shape= Hydrophobic
MIP contains too much
information to use
computationally in a
reasonable time
Field points provide
computationally
tractable framework for
electrostatic similarity
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Detailed electrostatics from XED
> eXtended Electron Distribution gives detailed electrostatic
interaction patterns
XED adds p-orbitals to get detailed representation of atoms
Separation of π- and σ- charges
enables modeling of substituent effects
= Positive = Negative
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Comparing structurally disparate molecules
PDB:2ogz PDB:3g0g
BioisosteresBioisosteric
groups
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Discover new directions for your project using bioisosteres
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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?
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Example: COX-2
> Search for Bioisosteres for cyclic lactone of Rofecoxib
Actives:
9 of the first 10 clusters
21 of the first 30 clusters
Search Common Dbs
87,225 frags
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Cluster,
Result
Nos
Cluster id Spark result 2D sim closest lit compd
10,12 0.52 Same, 60nM
13,19 0.509
7nM
32, 104 0.48 None
Cluster,
Result
Nos
Cluster id Spark result 2D sim closest lit compd
1,1 0.646
2,2 0.531
6.5uM
5,5 0.500 Same, 10nM
9,11 0.532
70nM
COX-2 Results
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1. Select a region to replace and remove these atoms
Spark’s approach
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Wrong distance
1. Select a region to replace and remove these atoms
2. Search database for matching fragments
> (geometric search only)
> (search runs on fragment conformations)
Spark’s approach
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1. Select a region to replace and remove these atoms
2. Search database for matching fragments
> (geometric search only)
> (search runs on fragment conformations)
Spark’s approach
Wrong angle
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1. Select a region to replace and remove these atoms
2. Search database for matching fragments
> (geometric search only)
> (search runs on fragment conformations)
3. Form products
> (minimize and add field points)
Spark’s approach
Good match
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> Produces more diverse, non-
obvious bioisosteres
> Avoids fragment scoring limitations
> Allows for electronic influence of
replacing a moiety on the rest of the
molecule and vice versa
> Allows for neighboring group effects
Whole-molecule scoring advantages
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Fragment sources
> Commercial catalogues> Sort fragments on frequency of occurrence
> ‘VeryCommon’, ‘Common’, ‘LessCommon’, ‘Rare’, ‘VeryRare’
> Literature reports (ChEMBL)> Sort fragments on frequency of occurrence
> ‘ChEMBL_Common’, ‘ChEMBL_Rare’, ‘ChEMBL_VeryRare’
Frequency roughly correlates with synthesizability
> Ring databases> Theoretical – ‘VEHICLe’
> Reagents> 17 transformations of reagents into R-groups
> eMolecules availability information
> Internal collections - optional module
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Files required:
1OIT.pdb
Pre-made files:
spark_1oit_results.fsp
Practical: Spark experiment starting from PDB
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Launch Spark
Click New Project
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Choose a project
Choose Search
for Bioisosteric
Replacements
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Load starter molecule from PDB
Click Protein
Choose 1OIT.pdb
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Load starter molecule from PDB
Click Open to
launch the protein
import wizard
Choose Let Spark
choose the
protonation state
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Split PDB into protein and ligand
Sort the table on
Structure to show the
ligand
Click on the ligand
structure
Click Use as Reference
Click Delete Waters
Click Import as Protein
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Check the ligand
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Check the ligand
Left-drag to lasso
the region to be
replaced
Click Next
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Allowed atom types at attachment point
You can choose
what atom type
you are willing to
accept at the
attachment point
Click Next
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Check protein is loaded
Click Finish
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Choose reagents to search and start
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Wait ~ 4.5 minutes
Wait or load?
Load
Spark_1oit_results
Click Cancel
Click Open
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Results
Explore how the
results can be
viewed
If you close any of these
results docks, you can get
them back from
Windows/Docks/…
or Windows/Reset
Layout
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Favorites
Click on the star to
mark a few results
as FavoritesDisplay the
favorites using
the right hand
button bar
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Display styles
> The 3D display is controlled by the display tool bar and chooser
> The chooser controls the domain of applicability for the display options
> Use the toolbar to:
> Change the colour of one structure
> Display the target in CPK
> Change the field points to tetrahedra for all results
Chooser Atom display style Atom color Surface toolbar
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Look at fields for favorites
Render the
+ve and –ve
surfaces and
compare to
reference
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Expansion tasks
> Create a radial plot profile
> MW 300-400
> SlogP 2-4
> BIF 65-80
> Order results by Radial Plot score
> Use Filters to
> Find all results with MW < 396
> Find all results with TPSA between 60
and 90
> Tagging
> Tag 2 results with 'Like'
> Tag 3 results with 'Good'
> Filter to find the 5 tagged results
> Create an image of 2 results in
PowerPoint
> Export 2 results to a drawing
program
> Send 1 result to Forge for editing
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Getting help
> Full PDF Manual
> Quick start and Tips sections to enable easy access
> Support
> Don’t be reluctant to ask for help!
> Cresset [email protected]
> Online meetings
> Phone
cressetgroup
Questions welcomed
Example files available from
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