introduction to spark - cressetcluster id spark result 2dsim closest lit compd 10,12 0.52 same, 60nm...

Introduction to Spark:

Discover new directions for your project using bioisosteres

Cresset European User Group Meeting – Workshops

June 2016

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Files for this workshop

> The files used in this workshop are available for download on

request

> Please send an email to enquiries@cresset-group.com stating the

name of the workshop

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Getting help

> Full PDF manual> Written to be useful

> Definitive descriptions of options

> Somewhat lengthy to dip into

> Support > Tell us where can improve

> Gain our input on your problem

> Cresset support@cresset-group.com

> Online meetings

> Phone

> Email

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Cresset technology and scientific approach

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Field points

3D Molecular Electrostatic

Interaction Potential (MIP)

Field Points

= Positive = Negative

= Shape= Hydrophobic

MIP contains too much

information to use

computationally in a

reasonable time

Field points provide

computationally

tractable framework for

electrostatic similarity

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Detailed electrostatics from XED

> eXtended Electron Distribution gives detailed electrostatic

interaction patterns

XED adds p-orbitals to get detailed representation of atoms

Separation of π- and σ- charges

enables modeling of substituent effects

= Positive = Negative

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Comparing structurally disparate molecules

PDB:2ogz PDB:3g0g

BioisosteresBioisosteric

groups

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Discover new directions for your project using bioisosteres

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> Increased novelty

> Find gaps in patents

> Rapid assessment of available

chemistry space

> Protect your Patents

> Scaffold hop using a db of

fragments

> Find new R groups from db of

available reagents

> New ideas

> Fragment growing

Scaffold hopping from Spark

“The best bioisostere application on the market”

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> Great results> Obvious

> Less obvious

> Completely novel

> Easy to use> Few clicks for an experiment

> Property profile not just activity> Radial plot properties

> Designed to share > Result tagging

> Get the best IP position

> Find freedom to operate even in

congested space

> Map out larger chemistry spaces –

deny freedom to competitors

> Get the best properties

> Find a back up series

> Avoid your own IP

> Generate leads from patents

> Quickly step through LO

> Avoid the ‘obvious’

> Link ideas to available reagents

Why Spark?

10

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Example: COX-2

> Search for Bioisosteres for cyclic lactone of Rofecoxib

Actives:

9 of the first 10 clusters

21 of the first 30 clusters

Search Common Dbs

87,225 frags

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Cluster,

Result

Nos

Cluster id Spark result 2D sim closest lit compd

10,12 0.52 Same, 60nM

13,19 0.509

7nM

32, 104 0.48 None

Cluster,

Result

Nos

Cluster id Spark result 2D sim closest lit compd

1,1 0.646

2,2 0.531

6.5uM

5,5 0.500 Same, 10nM

9,11 0.532

70nM

COX-2 Results

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1. Select a region to replace and remove these atoms

Spark’s approach

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Wrong distance

1. Select a region to replace and remove these atoms

2. Search database for matching fragments

> (geometric search only)

> (search runs on fragment conformations)

Spark’s approach

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1. Select a region to replace and remove these atoms

2. Search database for matching fragments

> (geometric search only)

> (search runs on fragment conformations)

Spark’s approach

Wrong angle

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1. Select a region to replace and remove these atoms

2. Search database for matching fragments

> (geometric search only)

> (search runs on fragment conformations)

3. Form products

> (minimize and add field points)

Spark’s approach

Good match

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> Produces more diverse, non-

obvious bioisosteres

> Avoids fragment scoring limitations

> Allows for electronic influence of

replacing a moiety on the rest of the

molecule and vice versa

> Allows for neighboring group effects

Whole-molecule scoring advantages

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Fragment sources

> Commercial catalogues> Sort fragments on frequency of occurrence

> ‘VeryCommon’, ‘Common’, ‘LessCommon’, ‘Rare’, ‘VeryRare’

> Literature reports (ChEMBL)> Sort fragments on frequency of occurrence

> ‘ChEMBL_Common’, ‘ChEMBL_Rare’, ‘ChEMBL_VeryRare’

Frequency roughly correlates with synthesizability

> Ring databases> Theoretical – ‘VEHICLe’

> Reagents> 17 transformations of reagents into R-groups

> eMolecules availability information

> Internal collections - optional module

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Files required:

1OIT.pdb

Pre-made files:

spark_1oit_results.fsp

Practical: Spark experiment starting from PDB

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Launch Spark

Click New Project

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Choose a project

Choose Search

for Bioisosteric

Replacements

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Load starter molecule from PDB

Click Protein

Choose 1OIT.pdb

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Load starter molecule from PDB

Click Open to

launch the protein

import wizard

Choose Let Spark

choose the

protonation state

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Split PDB into protein and ligand

Sort the table on

Structure to show the

ligand

Click on the ligand

structure

Click Use as Reference

Click Delete Waters

Click Import as Protein

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Check the ligand

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Check the ligand

Left-drag to lasso

the region to be

replaced

Click Next

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Allowed atom types at attachment point

You can choose

what atom type

you are willing to

accept at the

attachment point

Click Next

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Check protein is loaded

Click Finish

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Choose reagents to search and start

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Wait ~ 4.5 minutes

Wait or load?

Load

Spark_1oit_results

Click Cancel

Click Open

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Results

Explore how the

results can be

viewed

If you close any of these

results docks, you can get

them back from

Windows/Docks/…

or Windows/Reset

Layout

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Favorites

Click on the star to

mark a few results

as FavoritesDisplay the

favorites using

the right hand

button bar

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Display styles

> The 3D display is controlled by the display tool bar and chooser

> The chooser controls the domain of applicability for the display options

> Use the toolbar to:

> Change the colour of one structure

> Display the target in CPK

> Change the field points to tetrahedra for all results

Chooser Atom display style Atom color Surface toolbar

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Look at fields for favorites

Render the

+ve and –ve

surfaces and

compare to

reference

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Expansion tasks

> Create a radial plot profile

> MW 300-400

> SlogP 2-4

> BIF 65-80

> Order results by Radial Plot score

> Use Filters to

> Find all results with MW < 396

> Find all results with TPSA between 60

and 90

> Tagging

> Tag 2 results with 'Like'

> Tag 3 results with 'Good'

> Filter to find the 5 tagged results

> Create an image of 2 results in

PowerPoint

> Export 2 results to a drawing

program

> Send 1 result to Forge for editing

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Getting help

> Full PDF Manual

> Quick start and Tips sections to enable easy access

> Support

> Don’t be reluctant to ask for help!

> Cresset support@cresset-group.com

> Online meetings

> Phone

> Email

cressetgroup

Questions welcomed

support@cresset-group.com

Example files available from

enquiries@cresset-group.com

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