Introduction to designing - PowerPoint Presentation

Slide1

Introduction to designing new molecules in Forge

Cresset India Symposium 2016Slide2

Find new ways to discover or view compounds and data that provide results which would otherwise be missedDeliver this new science in easy-to-use interfaces with minimal learning curvesGUIs, command lines, KNIME nodes, Pipeline Pilot components ….

Ligand based

applicationsForge, Spark, Blaze, Torch

Cresset application philosophySlide3

Detailed electrostatics from XEDeXtended

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

= NegativeSlide4

Cheeseright et al,

J. Chem Inf. Mod.,

2006, 665

Grant, Gallardo, Pickup,

J. Comp. Chem.

, 1996, 1653

Fields

0.66

Shape

0.98

Electrostatic and shape

s

imilarity

Combined

0.82

Score

Virtual

s

creening

s

caffold hopping

Pose

Bioactive conformation

hypothesis

SAR interpretation

molecule design Slide5

Comparing structurally disparate molecules

PDB:2ogz

PDB:3g0g

Bioisosteres

Bioisosteric

groupsSlide6

Understanding and using SAR to improve molecule design and intellectual propertySlide7

Understand structure-activity using ForgeUses ligand alignment as a basis for SAR interpretation

Ligands aligned to a reference or ‘template’ using

Electrostatics and shapeShape only

Substructure

Align single chemotypeDecipher complex SARUnderstanding design of new moleculesAligned many chemotypes

Virtual screening (small scale)

Relating activities from different series

SAR

transfer

Bioactive conformation hypothesisSlide8

Forge

design

workflow

Yes

Develop

pharmacophore

(

FieldTemplater)

Load

ligand

as

reference

‘Protein guided’ –electrostatics and shape

‘Ligand guided’ – field guided substructure

Align to

references

Build 2D

and

3D

QSAR Models

Use

score

for

virtual

s

creening

Look for 2D

and

3D activity cliffs

Score

designs

against

QSAR models

Design new

molecules

Summarize SAR in Activity Atlas Models

Design against Activity Atlas models

Summarize SAR in Activity Atlas

models

Build 2D

and

3D

QSAR models

Look for 2D

and

3D activity

cliffs (Activity Miner)

Ligand conformation

known

?

Use low energy conformation

NoSlide9

Launch

Forge

Click

New ProjectSlide10

Choose a project template

Click

Align MoleculesSlide11

Bring in reference molecule from protein

Click

ProteinSlide12

Bring in the protein

Click

Browse

Choose

1oit.pdb

Then click

OKSlide13

Protonation state

Click

Open

Choose

Let

Forge choose

the protonation

state

Then

click

NextSlide14

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 ProteinSlide15

Protein loaded

Click

NextSlide16

Load molecules to align

Click

Browse

Click

Open

Choose

cdk_test_IC50.sdf

Choose

Let

Forge choose

the protonation

state

Click

FinishSlide17

Align molecules

Click

Start

Choose

Normal

for both Conformation Hunt and AlignmentSlide18

Forge GUISlide19

Torch GUI

Main Toolbar

Style-Surface Chooser

Style Toolbar

Surface Toolbar

Radial Plot Control

Selection Toolbar

3D View

Info Bar

Storyboard window

Radial plot for selected molecules

Measurement Toolbar

Protein Toolbar

Filters window

Model window

Molecule Tiles

Molecule TableSlide20

StructuresTiles (Choose what data)Spreadsheet (Molecules)Project NotesGood for keeping track of what you’ve done

Filters

Finding the interesting molecules in a larger datasetStoryboardCapture a scene for posterity

Create a StoryAn interesting molecule

Radial PlotSummary for individual and multiple moleculesAlso present in Molecules and Tiles windows

Radial Plot Properties

Set up the radial plot

Use to set a project profile for scoring

QSAR Model

Controls the view of the QSAR model

Only useful with QSAR models

Choose your windows and layoutSlide21

Simplified Forge GUI

Storyboard window

Filters window

Molecule Table

Project notesSlide22

Molecules tableSlide23

Choosing what is shown in the 3D View

Show/Hide all molecules marked as favorites

Show reference molecule separately

Show/Hide all reference molecules

Show/Hide all molecules marked as protein molecules

Show molecules in a grid display rather than overlaid

Show/Hide selected molecules

Show/Hide Model featuresSlide24

Separate vs GridSlide25

Choosing how structures are displayed in the 3D View

Reset display

Show field points as:

Spheres

Tetrahedra

Cubes

….

Show/Hide hydrogens

Show/Hide XED atoms

Show/Hide Field points

Show/Hide structure

Change molecule color

Show structure as:

Lines

Thin sticks

Sticks

…

Label atoms or structure

Show/Hide hydrophobic Field

Remove all surfaces

Show/Hide positive Field

Show/Hide shape Field

Show/Hide solvent surface

Show/Hide negative Field

Change Field contour levelSlide26

The Chooser

and

and

andSlide27

Alignments and scoresSlide28

Design a new molecule based on the 1PXO ligand

1pxo

ligand is a fragment that can be ‘grown’ to approximate the field points associated with the phenyl sulphonamide in the referenceSlide29

Edit a copy of the 1PXO ligand

Right-click

on the

1pxo

ligand and choose

Edit a Copy

. Slide30

Molecule Editor

Right-hand button bar

has buttons for showing/hiding reference molecule, protein, and 3DQSAR model information

Sim

score shown in lower left-hand corner

Change the title

– 1pxo+Ph

– or make any notesSlide31

Grow the molecule using the Molecule Editor

Phenyl has been added to the terminal amine, and the bond rotated to get a similar conformation to the reference

Sim

score has increased

Press

Process

to conformation hunt and align the new moleculeSlide32

Alignment resultsSlide33

Find the new molecule and create a new Role

Find your new molecule

Right click on itSelect ‘Set Role  New Role’

Role Name  ‘Designs’

Description  ‘Molecules that have been designed but not made yet’

Examine Tile or Molecules window – find the new role and new moleculeSlide34

Visualize in the protein active siteSlide35

Coloring in the Molecules TableSlide36

Radial Plot and multi-parameter optimization

Radial plot allows for simultaneous viewing of numerical parameters

Customizable

By default, the smaller the area encased in green, the better the propertiesSlide37

Reference molecule choice

Choose the smallest (in field terms), most active compound (ligand efficiency)

In field space, charged groups are BIG – e.g. CO2 >>>>>> iPr

in field space

remove extraneous groups (e.g.: solubilizers)Multiple, pre-aligned references can work well

Use extra references to add information

Electrostatic

ShapeSlide38

Expansion tasks

Create a radial plot profile

MW 300-400SlogP 2-4

BIF 65-80Order 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 editingSlide39

Combine multiple numerical properties into a single scoreCreate a project profile for physico-chemical (or other) properties

Add properties from external server

Color by fit to profile2D

3DInteractive scatter plots and histogramsStoryboard to record important 3D viewsSplit datasets into roles

Tag molecules across rolesRecord experiments in Project notesDesign in 3D

Reject designs that make no sense in 3D

No protein required – wholly ligand based approach

Protein can be used data used in visualization

Electrostatic focus reveals more detail than available from 2D design

Enables hypothesis led design

Torch featuresSlide40

Questions welcomed support@cresset-group.comSlide41

Paste from chemistry drawing app

Design in 3D

Guided by reference structureGuided by Activity Atlas modelGuided by QSAR model

Rapid feedbackIn editorProper alignment to references

Physico-chemical propertiesRecord keepingNotes on each designNotes on the project

Core Torch task: Design of new

c

ompoundsSlide42

Design molecules with TorchSlide43

Radial plot allows for simultaneous viewing of numerical

parameters

By default, the smaller the area encased in green, the better the

properties

CustomizableMany numbers (up to ~15 works ok)

Default and specific profiles

Overall fit summarized into a score

Radial Plot and multi-parameter

o

ptimization

Good

Fair

PoorSlide44

Coloring in the Molecules TableSlide45

Activity cliffs reveal regions of acute SARActivity Miner finds and (tries to) explain activity cliffsOur focus is on understanding, not just detectionUnderstanding leads to improved hypotheses and designs

Data manipulation challenging

Small datasets result in large number of datapoints

Torch o

ptional module: Activity MinerSlide46

Protein or ligand-based alignment?

Field-based alignment

Uses Cresset electrostatic, shape and hydrophobic field points to alignScored 50% field-based similarity with 50% shape similarity

Independent of chemical structureMeaningful score comparisonsBetter for libraries that have structurally diverse compoundsSlide47

Protein or ligand-based alignment?

Maximum common substructure alignment

Good for a library with a common core or concentric series

Common structural features in database molecules are mapped onto conformation of corresponding features in reference moleculeAll other parts of the molecule are conformationally huntedField/shape based scoring

Score comparisons between molecules less usefulSlide48

Electrostatic and shape SAR from aligned ligandsSlide49

Similarity3D Activity Cliffs

Disparity (

Δactivity / 1-similarity)Slide50

Nearest Neighbors according to 3DSlide51

Nearest Neighbors according to 2DSlide52

Selectivity through multiple activities