future developments for forge™, blaze™ and pickr™€¦ · > save views in the storyboard...

Future Developments forForge™, Blaze™ and PickR™

Dr Giovanna TedescoHead of Products, Cresset

© CressetCONFIDENTIAL

How do I ….

Import Electrostatic Complementarity™ scores in Forge?

Display cation-pi interactions in Forge?

Set Spark to make an H-bond interaction with this residue?

Post-process Spark results in Flare?

Remember which product to use?

User feedback ….

I would like to have ….

New science

Simplicity of product offering

Integration across products

Easier access to our methods

Easier access to third party and in-house methods

Flexibility of licensing

User friendliness

I want to ….

Do all my modeling work from the same GUI

Score replacements directly against the protein in Spark using a docking-scoring-function-like capability

Export radial plot properties in Spark (it works really well in Forge)

Compare Activity Atlas™ maps against multiple proteins to understand selectivity

Use ligand alignment in Flare

Run virtual screenings using also docking and shape

Do monomer selection in 3D by similarity and diversity


> Advantages> Simplification of product offering> A single, integrated GUI> Ligand- and structure-based methods

working in synergy> Full access to all functionality through the

Python API> Modern, user friendly architecture> Flexible, modular license structure

> Challenges> Safeguard the user experience> Keep it easy to use> Keep learning curve at a minimum

Integrate Forge, Spark and PickR into Flare?


Ligand alignment

ElectrostaticShapeSubstructure

Small scale virtual screening

Interactive 3D molecule designInteractive 3D molecule design

Bioactive conformation hypothesis

(Pharmacophores)

SAR analysisQualitativeQuantitative

Small scale virtual screening

Ligand alignment

ElectrostaticShapeSubstructure

Cresset desktop solutions

ElectrostaticsProteinLigandComplementarity

CustomizableMenusMethodsForce fieldsScripts

Binding EnergeticsFree Energy PerturbationWater position and stabilityLigand binding from WaterSwap

Scaffold hoppingR-group design

Ligand-based virtual screening of millions

Pick electrostatically diverse monomers

DynamicsProteinLigand

Ligand dockingCovalentConstrainedTemplated


An informative approach to SAR analysis and molecule design

Modern ligand-based workbench


> Decipher Structure-Activity Relationships (SAR) and communicate the results> Qualitative SAR analysis with Activity Miner

and Activity Atlas

> Create predictive quantitative SAR models> Field QSAR and Machine Learning models for

regression and classification

> Build detailed hypothesis of bioactive conformation> Work in 3D on targets with no structural

information> More detailed than pharmacophores

> Design and score in 3D> Use electrostatics/shape and SAR

information to guide design> Use QSAR models predictions to score

designs

> Property profile not just activity> Radial plots/Multi-parameter scoring> Add data from bespoke models or

services

> Virtual screening at a small scale> Score by electrostatic/shape similarity

towards known active molecules> Score by QSAR model predictions

Ligand-focused workbench for SAR and design


> Started with Flare V3> Forge Design ligand-based alignment

> Will complete in Flare V5 (2Q 2021)> Forge advanced alignment options> Qualitative SAR analysis

> Activity Miner and Activity Atlas> Quantitative SAR analysis

> Field QSAR and Machine Learning> Field Templater bioactive conformation

hypotheses> Conformation Explorer> All the nice GUI features

> The benefits for users:> A single, integrated GUI: ligand- and

structure-based methods working in synergy

> Modern, user friendly architecture> Full access to all functionality through the

Python API

The next release of Forge: full integration into Flare


A sneak peek of Flare V5: Activity Miner

Activity View

Disparity Matrix

Top pairs

Multiple AM projects

Cluster View

Multiple comparison ligands


Everything I can do in Forge

> And also:> Save multiple AM projects in the same

Flare project> View multiple comparison ligands at the

same time> Add ligands at any time> View against different proteins in the

same project> View Activity Atlas maps> View Field QSAR coefficients> Save views in the Storyboard

Full access to the Flare GUI

> Change ligands and protein display at any time

> Show different protein surfaces> Protein Interaction Potentials> Electrostatic Complementarity> Hydrophobicity

> Show Electrostatic Complementarity maps for ligands

> Show ligand-protein interactions> H-bonds, clashes> Aromatic-aromatic, cation-pi, salt

bridge, sulfur-lone pair, halogen bonds> ….

Activity Miner in Flare: now I can do…


Dramatically increase your wet screening hit rate at a fraction of the cost

Advanced ligand-based virtual screening


> Find diverse new structures> Multiple methods generate more

diversity> More detailed than pharmacophores> Search Electrostatics and Shape> Search Shape only> Use field and pharmacophore constraints

> Choice of similarity metrics> Dice, Tanimoto and Tversky

> Excluded volumes from protein

> Full database management system> Creates conformations> Takes care of new and deleted structures> Removes duplicates> Populates stereocentres> Organize molecules in collections> Spike retrieval

> Easy and fast> Wizard-based web interface> Search 10M compounds in 5 clicks

> Run on Linux CPU or GPU cluster> Software, service or rental

Virtual screening with Blaze


> ‘Blaze’ ligand-based virtual screening> Field and pharmacophore constraints> Excluded volumes from protein> Choice of similarity metrics

> Lead Finder high-throughput docking> Docking constraints

> Shape and pharmacophores> 2D fingerprint searches> …..

> Currently at 50-100M

> Initial release date: 2Q 2021

Multiple VS methods Advanced list handling

> Sub-structure filters> Physico-chemical filters> List combination operations

> And/or> Consensus scoring

Future plans for Blaze: comprehensive virtual screening platform

Increase capacity to 1Bn+


High quality libraries and better intellectual property



> PickR is a monomer selection tool for library design> Choose ‘diverse’ reagents from a larger

set> Uses shape and electrostatics to

calculate diversity> PickR picks diverse R-groups from a

list > Use electrostatic diversity as a key

component in monomer choice

> Use PickR to improve IP position:> Gain a wider coverage of chemical

space in hit generating library design> Gain a wider coverage of chemical

space in hit follow up> Combine 3D with 2D similarity for

optimal space coverage


PickR V1: released Spring 2019


How does it work?

> Compares every reagent against every other and calculates their electrostatic and shape similarity

> Generates a matrix of similarity values> Clusters the results

> Multi-stage process> Calculate conformations for reagent A and reagent B> Align confs of A and confs of B on a specified bond (SMARTS pattern)> For each pair of confs rotate A relative to B and report the max 3D

similarity value> Cluster the resulting similarity matrix (K-medoids)


Results – 3D descriptors generate different relationships

2D Distance

3D D

ista

nce

2D (MACCS) vs 3D similarity for 200 boronic acids

2D specific pairs

3D specific pairs


Results fit with chemical intuition

2-Ar-4-pyridyl boronics 3-(2-H-bond acceptor-Ar)-phenyl boronics


PickR vs. Spark: two sides of the same coin

> Spark R-group exploration> Works in 3D

> Electrostatics and shape> Selects R-groups by 3D similarity towards

a starter molecule> Has a user-friendly GUI for experiment set-

up and result analysis

> Enumerates the array> Does not support libraries

> PickR monomer selection> Works in 3D

> Electrostatics and shape> Selects R-groups by 3D diversity

> Command-line only> Experiment set-up still easy> Browsing the results could be easier

> Does not enumerate the array/library> Has to be done as a separate step

> Future plans for PickR: > Give it a GUI, but keep the command-line functionality for working on large numbers> Support to library enumeration and design> Integrate both methods into a comprehensive library design platform within Flare


In conclusion…

> Users feedback and needs are a key factor of Cresset software development

> We hear what you say!

> Use the software: evaluate, use, criticize, ask for more

> Work with us to make it your software of choice


cressetgroup

[email protected]

Questions welcome

The desktop applications team:Mark, Nigel, Paolo, Ken, Rosie, Mary, Joy and Tim

The application scientist team:Nathan, Stuart, Sylvie, Rick

future developments for forge™, blaze™ and pickr™€¦ · > save views in the storyboard...

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