Giovanna Tedesco, Tim Cheeseright...New in Forge 10.4 > New (Q)SAR analysis methods > Activity...
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What is new and different in Cresset software Giovanna Tedesco, Tim Cheeseright
Transcript of Giovanna Tedesco, Tim Cheeseright...New in Forge 10.4 > New (Q)SAR analysis methods > Activity...
What is new and different in Cresset softwareGiovanna Tedesco, Tim Cheeseright
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Discover new directions for your project using bioisosteres
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Spark
Finding bioisosteres by replacing sections of the molecule
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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
New October 2014> Tile view of results> Tag results> SMARTS filtering> New databases
> More fragments
> New and more reagents> More control over
minimizations
Spark: New/improved
Available in GUI, Command Line, KNIME, Pipeline Pilot
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Understanding and using SAR to improve molecule design and intellectual property
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Forge workflow
Build (Q)SAR model
[Field QSAR, kNN, Activity Atlas]
Yes
‘Protein guided’ –shape and electrostatics
‘Ligand guided’ – field guided substructure
No
Evaluate designs against 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
[Activity Miner, Activity Atlas]
Design new molecules
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New in Forge 10.4
> New (Q)SAR analysis methods> Activity Atlas, kNN
> New features and improved UI> QSAR Model dock: save, analyse, visualise multiple
(Q)SAR models in the same Forge project> Storyboard> Forge Processing dialogue > Preferred alignments> Interaction with Blaze> Activity Miner UI> Improved visualization of protein active site> Export of MEP> Combine selected molecules
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Also new in Forge10.4
> Multi-parameter optimization> Create project profiles using Radial plot (in 10.3)> Add a weighting to each property and combine into a single score> Colour Columns and Molecules by Radial Plot score> Colour columns and molecules by any property (e.g. Activity)
> Tile View> Data from an external server> Filter on drawn substructure > Improved Plotting
> Histograms > Second y-series in scatter plots
> Tags> Roles> Lots of GUI improvements and tweaks
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> Qualitative SAR (3D)> Requires alignments> Fields/shape similarity> Activity Miner > Activity Atlas
> Qualitative SAR (2D)> Does not require
alignments> 2D fingerprints and
pharmacophore fps available
> Activity Miner
> Quantitative SAR (3D)> Requires alignments> Fields/shape similarity> Field Based 3D-QSAR> kNN
> Quantitative SAR (2D)> Does not require
alignments> 2D fingerprints and
pharmacophore fps available
> kNN
(Q)SAR analysis in Forge
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New QSAR Model Dock
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QSAR Model selector
QSAR Model graphs and information
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Field based 3D-QSAR graphs, views and info
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Viewing the field QSAR model
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Viewing the field QSAR model
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Activity Atlas
> Activity Atlas is a probabilistic method of analysing Structure Activity Relationships> Uses a Bayesian approach to take a global view of the
data> Qualitative only (no predictions)> Designed to be used with data sets of
reasonable size (>20 mols)> In particular, if the training set has <10 molecules, all
molecules are fairly ‘novel’> Works in 3D, with aligned molecules, so we
should consider when the alignment is not correct
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Activity Atlas: Three different analyses
> Map properties onto a grid around the molecules> Three different analyses, to answer three different
questions1. Average of actives: what do active molecules have in
common?> Look at all active molecules, and map their fields
2. Activity Cliff Summary: what do the activity cliffs tell us about the SAR?
> Look at all pairs of molecules, and map their field differences
3. Regions explored analysis: where have I been? For a new molecule, would making it increase our understanding?
> Look at all molecules, and map their fields> Done in a probabilistic fashion, taking account of the
probability that a molecule is correctly aligned
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Activity Atlas average of actives
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Active molecules generally have a positive field here
Active molecules generally have a negative field here Average shape of active
molecules
Active molecules generally make hydrophobic interactions here
What do active molecules have in common?
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Activity Atlas activity cliff summary
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Small halogen required here (sterics + negative)
Larger substituents disfavoured here
Strong signal that benzyl here is favoured (steric shape, electrostatic pattern)
No strong SAR here
Electron deficient aromatic favored
No information on NH3+ - always present!
What do the activity cliffs tell us about the SAR?
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Activity Atlas activity regions explored
> From the 'regions explored' analysis, we know what steric/electrostatic interactions we have tried where
> We can map proposed molecules against this, to see if they are doing anything new> Creates a 'novelty' score
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Where have I been? For a new molecule, would making it increase our understanding?
Electrostatics Hydrophobics and shape
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kNN
> Distance metric to use> (1-similarity)> kNN in Forge can use both 3D and 2D metrics
> Choice of k> Cross-validation
> Weighting schemes> Lots of options in the literature> Constant> Inverse distance> e-distancen
> Try them all and use the best
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Predicted activity = average activity of k neighbours
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kNN graphs and information
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New features: The Storyboard
> The Storyboard record scenes from the 3D window that can be recalled easily
> All details are recorded: presence or absence of measurements, surfaces, models, the view center the selected molecule etc.
> Facilitates communication of a project to colleagues through recording of a story consisting of several scenes
> Useful for recording important results or for analyzing different models such as those build against different activities
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New Processing dialog
> Completely re-designed to better handle different model building choices and options
> More intuitive to use> Information and warning notifications given at the bottom of the dialog
window
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Visualization of protein active site
> Protein active site radius control in Protein Display Toolbar
> Display H-bonds and steric clash separately> Measurements can be individually cleared
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Interaction with Blaze: Running a Blaze search
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Interaction with Blaze: Download search results
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Activity Miner
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Now works also with non-aligned molecules
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Improve molecule design and intellectual property
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Forge workflow
Build (Q)SAR model
[Field QSAR, kNN, Activity Atlas]
Yes
‘Protein guided’ –shape and electrostatics
‘Ligand guided’ – field guided substructure
No
Evaluate designs against 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
[Activity Miner, Activity Atlas]
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
Evaluate designs using QSAR model
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New in Torch 10.4
> Multi-parameter optimization> Create project profiles using Radial plot (in 10.3)> Add a weighting to each property and combine into a single score> Colour columns and molecules by Radial Plot score> Colour columns and molecules by any property (e.g. Activity)
> Tile View> Data from an external server> Filter on drawn substructure > Improved Plotting
> Histograms > Second y-series in scatter plots
> Tags> Roles> Minimization new design in protein active site> Lots of GUI improvements and tweaks
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> Quick way to see many structures
> Large, medium and small
> Any data on tile> Radial Plots> Text (e.g. ID)> Favourite status> Notes> Tags
> Sort on any column / property
> Configure defaults in Preferences
Tile view
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> Configure Torch to send data to server that returns properties> Preference setting
> Torch sends smiles strings
> Receives property: value pairs in JSON format
> Use for your logP/TPSA> Off target QSAR
models> ….
Your properties
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Filter on substructure
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Type your own
Click to draw
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Scatter Plots Histograms
Plotting
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Interactive selections on all plots
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Notes, tags and roles
> Project Notes since FieldAlign> Promoted to separate window for
recording experimental details> Molecule Notes arrived in 10.2
> add to tiles to make more visible> Tags introduced in Spark 10.3
> Custom label for any set of molecules> Use in filtering or subsetting
> Roles introduce in Forge 10.0> Molecules exist in roles – use to subset
data
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Multi-parameter optimization
> Which is the best molecule?> Not necessarily the most active
> Radial Plot shows a graphical representation of properties and their fit to the project profile
> In this release we complement the graphics with a single numerical score> Don’t always want the properties to be weighted evenly> Different importance of different properties in different
projects> Graphical representation and numerical scoring may differ
> Colour molecules, columns, and radial plot by score
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Radial Plot and MPO
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Good
Middling
Poor
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By Radial Plot By Activity
Color molecules
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