new features in cresst products
TRANSCRIPT
New Features in Cresset’s products
Focused towards Medicinal Chemists
Computational Chemists
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
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
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NN
Br
F FF
SH2NOO
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
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Alignment, Scoring and Comparisons
Clique based alignment
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Alignment, Scoring and Comparisons
Clique based alignment
Fields0.66
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Alignment, Scoring and Comparisons
Fields0.66
Shape0.98
Cheeseright et al, J. Chem Inf. Mod., 2006, 665
Clique based alignment
Grant, Gallardo, Pickup, J. Comp. Chem., 1996, 1653
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Fields0.66
Shape0.98
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
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Effective ligand based virtual screening
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> 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
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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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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 FastCliquerefinement/search
> REST interface > Searching> Database update
> Integration to Desktop tools
> Chiral enumeration> For unspecified chirality
Blaze – New/Improved Features
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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 accuracyWe want to replace the finger print stage with
something better
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Clique refinementDistance matrix of field points used to construct alignments
Many alignments Scoring used to find the
best
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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
refinementModify parameters for Clique refinement to
optimize for time vs accuracyRecover accuracy with the Simplex refinement?
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> 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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FastClique analysis - typical results
% FieldPrintRefined (X)
% top hits in Clique
% top hits in FastClique
30% 66 6240% 73 6950% 77 74 60% 82 8070% 86 8480% 90 8890% 95 92
100% 99.6 97
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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 hoursFast 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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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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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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Using the RESTapi in Forge 10.3
> Searching:
> Result browsing and downloading
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Understanding and using SAR to improve molecule design and intellectual property
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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
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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
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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
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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
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> 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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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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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
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Reagent Databases in Spark
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sparkV10
Finding bioisosteres by replacing sections of the molecule
O
SO
O
O
SO
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N
O
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S
SO
O
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O
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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
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> 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
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{ 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 $n _ 52 _ _
> _ _ delete " ;
delete-H > _ # ;
delete > # ;
~ = any bond& = and, | = orc = connections (c1 etc)$n = set atomic number
> = assign a property_ = do nothing“ = repeat last action# = remove atom
Anatomy of a Reagent Pattern
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Using the Reagent Importer
> Command Line (sparkdb)> Specify Reagent processing script as an option
> GUI> Switch to the Database Creator
> Database menuCreate Database
> Show options> Fragmentation mode
Reagent importer
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