1. New Features in Cresset’s products

2. Focused towards Medicinal Chemists
Computational Chemists

3. Simple Viewer 2D  3D conversion
3D Design tool, SAR interpretation
Bioisostere/Idea Generator, R Group explorer
SAR interpretation & Activity Cliffs, 3D Design,
3D QSAR, Pharmacophore modeling
Virtual Screening
Ligand minimizer, Conformation explorer

4. V10.2, Next Release June 2014
V10.2, Next Release June 2014
V10.2, Next Release October 2014
V10.2, Next Release June 2014
V10.2, Next Release 2015
V3.0, Next Release July 2014

5. © Cresset
N
N
Br
F F
F
SH2N
O
O
3D Similarity using Shape and Electrostatics
> Condensed representation of electrostatic, hydrophobic
and shape properties (“protein’s view”)
 Molecular Field Extrema (“field points”)
3D Molecular
Electrostatic
Potential (MEP)
Field Points
= Positive
= Negative
= Shape
= Hydrophobic
2D

6. © Cresset
Alignment, Scoring and Comparisons
Clique based
alignment

7. © Cresset
Alignment, Scoring and Comparisons
Clique based
alignment
Fields
0.66

8. © Cresset
Alignment, Scoring and Comparisons
Fields
0.66
Shape
0.98
Cheeseright et al,
J. Chem Inf. Mod., 2006, 665
Clique based
alignment
Grant, Gallardo, Pickup,
J. Comp. Chem., 1996, 1653

9. © Cresset
Fields
0.66
Shape
0.98
Cheeseright et al,
J. Chem Inf. Mod., 2006, 665
Grant, Gallardo, Pickup,
J. Comp. Chem., 1996, 1653
Alignment, Scoring and Comparisons
Clique based
alignment
Combined
0.82

10. © Cresset
Effective ligand based virtual screening

11. © Cresset
> Diverse new structures
> New uses for existing
drugs
> Search a database for new
structures
> Uses a Linux CPU or GPU
cluster
> Software, Service or Rental
Virtual Screening with Blaze
11

12. © Cresset
About Blaze
> Full VS system
> Compound & collection management
> User & project permissions
> Integrated into SGE or LSF
> Search history and archiving
> Choice of interface
> Web browser
> Command line
> REST API
> Access from Pipeline Pilot, KNIME etc
> Access from Forge, Torch
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13. © Cresset
New in 2013
> Search from Forge/Torch
> Single web page for
experiment setup
> Sub-setting of compound
collections
> GPU acceleration of
searches
April 2014
> New FastClique
refinement/search
> REST interface
> Searching
> Database update
> Integration to Desktop
tools
> Chiral enumeration
> For unspecified chirality
Blaze – New/Improved Features

14. © Cresset
Tiered Approach to Searching
> Field Finger Print
> Crude but gets rid of poor matches
> ‘Clique’
> Alignment and 1 time score
> ‘Simplex’
> Optimised alignment – equivalent to Forge routine
We want improved speed but maintain accuracy
We want to replace the finger print stage with
something better
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15. © Cresset
Clique refinement
Distance matrix of field points used to construct alignments
Many alignments Scoring used
to find the
best
15

16. © Cresset
Clique has many parameters
> Minimum size of field point to include
> Types of field point to include
> Maximum number of cliques to generate
> …
> Parameter choice a balance with the emphasis
on the best alignments not the shortest time
> Correct option in Forge and in final Simplex
refinement
Modify parameters for Clique refinement to
optimize for time vs accuracy
Recover accuracy with the Simplex refinement?
16

17. © Cresset
> What % of the top scoring results do we recover using
clique and fastclique?
> Assume top 1% simplex results are the gold standard
> Refine top 10% of clique results in simplex
> Measure % of top hits recovered
> Repeat for many search queries
FastClique analysis
FieldPrint all
Clique or
FastClique X %
Refine top 10%
in Simplex
Measure % top
hits recoverd
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18. © Cresset
FastClique analysis - typical results
% FieldPrint
Refined (X)
% top hits in
Clique
% top hits in
FastClique
30% 66 62
40% 73 69
50% 77 74
60% 82 80
70% 86 84
80% 90 88
90% 95 92
100% 99.6 97
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19. © Cresset
FastClique Timing
Number of
compounds
FieldPrint FieldClique FieldSimplex
Typical Time
using 250
CPU cluster
Normal Mode 4 500 000 1 500 000 150 000 4 hours
Fast Mode 4 500 000 3 000 000 150 000 2.3 hours
> Test set of molecules of varying size
> Original Clique 13.3s
> FastClique 2.9s
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20. © Cresset
FastClique Conclusions
> Drop in accuracy can be countered by taking
more FieldPrint results forward
> Greater throughput even when doubling the
numbers in the Clique refinement
> Recommended for all users
> Set your defaults in your Blaze profile
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21. © Cresset
Blaze RESTapi
> New interface with access to all Blaze methods
> Updating collections
> Searching
> Retrieving results
> http://blaze.cresset-group.com/blaze/ui/rest.cgi
> Access from standard ‘KREST’ Knime nodes
> Access from new Cresset Pipeline Pilot
components
> Access from Forge & Torch (V10.3)
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22. © Cresset
Using the RESTapi in Forge 10.3
> Searching:
> Result browsing and
downloading
22

23. © Cresset
Understanding and using SAR to improve molecule design
and intellectual property

24. © Cresset
Forge Workflow
Build 3D QSAR
Model
Yes
‘Protein
guided’ –
shape and
electrostatics
‘Ligand guided’
– field guided
substructure
No
Score Designs
against 3D
QSAR Model
Ligand
conformation
Known?
Develop
Pharmacophore
with FT
Use low energy
conformation
Load Ligand as
Reference
Align to
References
Use Score for
Virtual
Screening
Look for 2D &
3D activity cliffs
Design new
Molecules

25. © Cresset
Torch Workflow
Ligand
conformation
Known?
Load
Pharmacophore
Generated with
Forge
Load Ligand as
Reference
Look for 2D &
3D activity cliffs
Yes
‘Protein
guided’ –
shape and
electrostatics
‘Ligand guided’
– field guided
substructure
No
Align to
References
Design new
Molecules
Score Designs
against 3D
QSAR Model

26. © Cresset
New in 2013
> Activity Miner Module
> csv import of molecules or
data
> Upload ligand/protein pair
to Blaze
> Convert protein atom to
Field point
> Prune protein to just
active site (view only)
> Spin/Rock and Fullscreen
June 2014
> Multiple Activities
> 3D QSAR models
> Multiple activities in Activity
Miner  Selectivity Cliffs
> Radial Plots
> Graphing
> Integrated FieldTemplater
> …
> Blaze search browsing +
fetching
Forge - New/Improved + Planned Features

27. © Cresset
New GUI Features
> Integrated FieldTemplater & ftemplater command
line
> Better protein handling and display
> Ribbons, Active site only (button)
> New wizard
> Cleaner, modern look
> Plotting
> Scatter plots of any values
> Radial plots
> Summarize properties in radial plots
> Activity Manager
> Script editor
27

28. © Cresset
> Use multiple activities
> QSAR models
> Activity Miner
> Set average assay error for each activity
> ‘Primary’ and ‘Secondary’ activites used in table to
calculate LE, LLE
Activity Manager
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29. © Cresset
Columns Script Editor
> Javascript interface to column and molecule data
> Comes with examples
> More on our website
> E.g.
> Remove the ‘>’ symbol from all activities
> Color columns based on values
> Convert categorical activity into a numerical value
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30. © Cresset
New in 2013
> Reagent Databases
> Database Categories
> New (smaller) databases
> Radial plot of properties
> “Send to” menu to
improve integration with
Forge/Torch
> New “attachment type”
column for all fragments
Planned – October 2014
> Suggestions welcome!
> Current list:
> Improved tracking of
fragments through
databases
> Library design module
> Rapidly explore multiple R
groups from available
reagents
Spark - New/Improved + Planned Features

31. © Cresset
Reagent Databases in Spark

32. © Cresset
sparkV10
Finding bioisosteres by replacing sections of the molecule
O
S
O
O
O
S
O
O
N
O
O
S
S
O
O
O
O

33. © Cresset
Processing Reagents into Databases
> Intended to aid synthetically accessible choices
for a series
> Not assessing global “Synthesizability”
> Assume synthetic chemists already know how to
make most of the molecule
> Want to capture the origins of an R group
> Not trying to encode all chemical transformations
> Transformation can represent multiple chemical steps
> Extensible
> Add your own transformations
> Get us to write a new transformation for you

34. © Cresset
> 17 rules for conversion of R groups to fragments
> Only single attachment points
> Leaf groups not cores
> Rules written in “atpat”, Cresset’s version of smarts
Acids/acid
chlorides, delete
the -COOH
Acids where we keep only the
group attached to the acid
carbonyl. e.g. R-COOH -> R-*
Amines, keep the
N
Primary and secondary amines
where the N is the attachment
point such as in reductive
aminations e.g. R-NH2 -> R-NH-*
Aromatic halide Aromatic halides (Cl,Br,I) e.g. Ph-
Cl -> Ph-*
Current implementation

35. © Cresset
{ TITLE Acids/acid chlorides, delete the –COOH
DESCRIPTION Acids where we keep only the group attached to the acid
carbonyl.
DESCRIPTION e.g. R-COOH -> R-*
}
!H~C&c3&sp2<?mo>(~O&c1)~O|F|Cl|Br|I&c1 $n _ 52 _ _
> _ _ delete " ;
delete-H > _ # ;
delete > # ;
~ = any bond
& = and, | = or
c = connections (c1 etc)
$n = set atomic number
> = assign a property
_ = do nothing
“ = repeat last action
# = remove atom
Anatomy of a Reagent Pattern
35

36. © Cresset
Using the Reagent Importer
> Command Line (sparkdb)
> Specify Reagent processing script as an option
> GUI
> Switch to the Database Creator
> Database menuCreate Database
> Show options
> Fragmentation mode
Reagent importer

37. © Cressetsmarter chemistry | smarter decisions
Contact us
tim@cresset-group.com
Help, Training, Advice, Pizza
support@cresset-group.com
37