What’s New in Flare™ and Spark™...> Virtual screening > Complementary to other approaches > Diverse R groups for library design Cresset desktop solutions > SAR analysis >Qualitative

What’s New in Flare™ and Spark™

Dr Giovanna TedescoHead of Products, Cresset

© CressetCONFIDENTIAL

> Virtual screening> Complementary to other

approaches

> Diverse R groups for library design

Cresset desktop solutions

> SAR analysis> Qualitative> Quantitative

> Bioactive conformation hypothesis

> Beyond simple pharmacophores

> Interactive 3D molecule design

> Informed, effective design

> Ligand design focus> Protein-ligand docking> Protein-ligand minimization

> Electrostatics> Protein> Ligand> Electrostatic Complementarity™

> Binding energetics> Free Energy Perturbation> Water position and stability analysis> Ligand binding from Waterswap

> Customizable interface

> Accessible methods in a new application

> Scaffold hopping> R-group design

Ligand-based Structure-based


Enhance your designs using advanced approaches for protein-ligand analysis

Fresh insights into structure-based design with Flare


> Cresset workbench for structure-based design

> Analyse proteins and inform new molecule design

> New scientific capabilities extend the range of SBDD methods available> Electrostatic Complementarity™> Protein interaction potentials> Free Energy Perturbation> 3D-RISM with XED force field

> Robust enabling capabilities to support new workflows> Docking and scoring> Ligand-based alignment> Molecular Dynamics

> Modern, extensible, friendly user interface

> Customisable, scriptable, deployable science through Flare API and python command line

Fresh insights into structure-based design


> Flare V3: released November 2019> Flare V4: released May 2020

> Free Energy Perturbation> New and improved force fields

> Molecular Dynamics> ‘Forge Design’ ligand-based alignment> Improved docking and scoring

> Faster minimization algorithm> Multiple ligands minimization> Improved protein preparation> Improved handling of larger datasets> Improved handling of metals with the XED

force field

> New windows and tabs> Sequence similarity window> Structure check> Tile view> New Help tab

> New and improved Flare Python extensions and pyflare scripts

> Lots of GUI new features and improvements> Improved Contacts panel> Edit ligand and proteins the main window> Improved display of protein ribbons, including new

options for customizing colors and transparency> Improved handling of DNA/RNA> Protein surfaces as wireframe> Coloring in the Alignment and Proteins tables > Enhanced ligand filters> Synchronize 3D view> Send/Retrieve from Blaze

What’s new in Flare V3/V4


Based on OpenMM package

> Study conformational changes of proteins> Assess the stability of protein-ligand

complexes

> Choice of force fields:> AMBER/GAFF and AMBER/GAFF2> Open FF> Custom force fields parameters

> Explicit and implicit solvent> View results

> Plot of RMSD> Player to browse through frames

> Analyze results> Physical properties plots> Table of contacts> Measurements plots

New Molecular Dynamics


Molecular Dynamics

Player

Analysis tools

Resume calculation


Physical properties plots

Choose property to plot Export plot data


Monitor favorable protein-ligand interactions

Include weak H-bond interactions

Define threshold

Choose trajectory range


Plot measurements

Plot distances, angles and torsions

Export plot data

Define threshold


> Cresset’s patented ligand comparison method

> Align and score ligands based on:> Electrostatic and shape of reference

ligand(s)> Substructure

> Optional:> Use protein chains as excluded

volume> Use ligand field and

pharmacophore constraints to bias the alignment

‘Forge Design’ ligand-based alignment


> Decipher SAR of ligand series

> Generate new ideas on how ligands with different structures could interact with the same protein

> Ligand-based virtual screen thousands of compounds

> Generate sensible poses for Electrostatic Complementarity and FEP calculations

‘Forge Design’ ligand-based alignment


> Dock ligands> Predict binding pose and interactions

for new molecule designs> Improved ‘Accurate but Slow’ expands

GA exploration leading to improved results

> New covalent docking> Predict binding pose and interactions

for covalent inhibitors

New and improved docking methods

> New template docking> For docking and ensemble docking experiments> ‘Seed’ the docking run with a known template pose> Improved docking results for congeneric ligands

when the binding mode is known

> New docking constraints> Ensure that docked poses match relevant protein

interactions

> Ensemble docking> Consider active site flexibility in your docking

experiment> Template docking option available


Covalent docking

Michael acceptorsAlkynamidesNitrilesEpoxidesAzyridines/AziridinesSulfonyl fluoridesAlpha-halo ketones

Alpha-keto amides and estersBoronic acidsThiolsActivated esters

> Support for most popular warheads> Creates the covalent species and

docks to modified protein> Recognises multiple nucleophilic

residues:> CYS, LYS, SER, TYR

Covalent warhead Covalent species


New editing in the main 3D window

> Dedicated tab to ligand and protein editing

> Maintain full access to Flare GUI functions> Display an alternative protein> Display alternative ligands> Show/hide ligand and protein

surfaces> Change ligand and protein

appearance> Monitor contacts with

different proteins


> Python Extensions> Useful new functionality for all> Download Flare extensions from> https://gitlab.com/cresset/flare-python-

extensions

> Command line extensions> The vast majority of Flare’s functions

are scriptable using Python> ‘pyflare’ executable provides command-

line access> Download pyflare scripts from

https://gitlab.com/cresset/flare-python-pyflare

New and improved python extensions and scripts

https://gitlab.com/cresset/flare-python-pyflare


> Flare V5: release expected by 2Q 2021

> Complete integration of Forge into Flare> More in the next presentation…

> Planned new science and features:> Electron Density maps> QSAR models: machine learning on

imported descriptors> Automated determination of n. of

lambda windows for FEP> Custom parameters for OpenFF> Minimization of proteins based on

OpenMM> Ligand charge model from Astex> Improvement to MD: clustering of

trajectories, water analysis with GIST> RESP charges> Multiple processing in Flare

What’s next for Flare?


Explore chemical space and escape IP and toxicity traps

Generate highly innovative ideas for your project with Spark


> Scaffold hopping> Using fragments of real molecules or

commercially available reagents

> R-group exploration> Using commercially available reagents> Monthly updates for updated availability

information

> Advanced bioisostere replacement experiments> Replace in one molecule, score against a

second> Fragment growing and linking> Crystallographic water replacement> Macrocyclization

'The best bioisostere application on the market'

any atomNN

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Scaffold hopping

R-group replacement


> Release date: September 2020

> New calculation method to score Spark experiments via docking

> New fragment databases > From ChEMBL 26 and eMolecules screening

compounds> Monthly updates for reagent databases from

eMolecules building blocks

> New and improved database creation, update and search functionality

Spark V10.6

> Many other GUI improvements> In the Results tables, different attachment points

in a fragment get different labels> Better 2D structures> Improved Filters

> Prepared SMARTS patterns for common chemical groups/functionality

> Enable/disable> Import/export

> Import/export radial plot properties and custom settings

> New ‘Copy Column’ right-click option> ‘Clip Protein Only’ function> ……

> Improved command-line functionality> Command-line sparkcl searches can start from a

Spark project> Fragment linking, water replacement and

macrocyclization experiments from command line


> How it works:> Fragments matching geometric

constraints are scored to find best orientation within the protein active site

> Result molecules are docked into the active site of the protein

> Lead Finder docking and scoring algorithm

> Score only method, allowing pose optimization

> Poses ranked by LF rank score> Optional: set docking constraints to

ensure that the replacement fragments match the desired protein interactions

New ‘Docking’ calculation method


Ligand growing with docking and constraints

Docking constraint


Database creation> Remove boats and twist-boats during

database creation> Keep input conformations during database

creation also for pre-labelled reagents

Database search and update> Visible release date for all databases> Improved database update performance:

updates are now queued> Export to .csv of all database content> Search for database name in Spark Search

and Database Updater dialogues

New and improved Spark database functionality


cressetgroup

[email protected]

Questions welcome

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

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

What’s New in �Flare™ and Spark™Cresset desktop solutionsFresh insights into structure-based design with FlareFresh insights into structure-based designWhat’s new in Flare V3/V4New Molecular DynamicsMolecular DynamicsPhysical properties plotsMonitor favorable protein-ligand interactionsPlot measurements‘Forge Design’ ligand-based alignment‘Forge Design’ ligand-based alignmentNew and improved docking methodsCovalent dockingNew editing in the main 3D windowNew and improved python extensions and scriptsWhat’s next for Flare?Generate highly innovative ideas for your project with SparkSlide Number 19Spark V10.6New ‘Docking’ calculation method Ligand growing with docking and constraintsNew and improved Spark database functionalitySlide Number 24

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What’s New in Flare™ and Spark™...> Virtual screening > Complementary to other approaches > Diverse R groups for library design Cresset desktop solutions > SAR analysis >Qualitative