slides/cactvs/acswashington2000.ppt © ihlenfeldt 2000 c3c3 chemical visualization: the art of...

/slides/cactvs/acswashington2000.ppt© Ihlenfeldt 2000C3

Chemical Visualization:The Art of Drawing a Chemical Structure

W. D. Ihlenfeldt

Computer-Chemistry-Center

University of Erlangen-Nuremberg

Erlangen, Germany

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Topics

• Motivation

• Drawing One Structure

• Drawing a Set of Structures

• Visualizing Structure Attributes


Motivation: 3D is not Everything

3D structure displays are valuable tools, but ...

• limited to viewing part of structure

• unsuited for quick comparisons


Motivation: Defending 2D Plots

2D structure plots are still the core of of chemical information:

• show complete structure

• easy recognition of patterns

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Motivation

• So why can’t you just draw it with [your editor of choice] ?

The trend towards combinatorial libraries and structuredesign requires fast, reliable and automatic drawing of enormous numbers of compounds.

Unfortunately, 2D structure drawing is hard. [Helson, Rev. Comp. Chem., 13, 313, 1999]

• Because nobody wants to draw millions of structures!


Topics

• Motivation





The Rules

• Chemists know how a good plot should look like:

• Not a simple projection from 3D• Complex, ill-defined set of rules

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Basic Structure Data

• Draw a structure from connectivity• Atom/bond table• No coordinates to begin with• Often specified in linear notation such as SMILES O1C(/C=C/[C@@](/C=C/[C@@H](C(=C\CC[C@H]([C@@H]1C)C)/C)OC)(O)C)=O

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The Complications

• Orientation of ring systems

• Close atoms by colliding fragments

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• Rules for bridge systems

• Cages

The Complications


The Complications

• 1.3/1.4-embedded rings

• Crowded connection points


The Complications

• Choice of stereo attributes (wedges, etc.)

• Trans-bonds in rings

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H O

OOO

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A Simple Structure?

• dual 1.4-embedded rings• close contacts• no solution on 120º grid• 16-membered ring• implicit constraints• with +/- 60,90,45,35º angles• 814 naive patterns (4.3·1012)• max. for real-time response: 250.000 (2.5·105)

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Controlling the Number of Patterns

• closing distance and angle• cis/trans information• total distance criterium• full loop criterium • no clustering of non-60° angles• pseudo energy selector• favoring 60°, symmetry


A Simple Structure?

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Isis/Draw 2.2

ChemSketch 3.5

ChemDraw 5.0

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NCACTVS 3.113


More Examples

Symmetry-preserving

optimization by

synchronous bond

bendingN

Ni

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NN


More Examples

Optimization by

bond shortening

H N

NOH

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H

ON

H

O

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H

O

H N

NO


More Examples

Cage system

analysis

(not a template)OHHHOHHHHHHHHHHHHH

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More Examples

Complex ring

system and bond

arragenment

analysis

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O HH H

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More Examples: Complex Ring Systems

C\C(C(CC)C(C)/C([H])=C/C([H])=C(CO3)/C2(O)C3C(OC)C(C)=CC2C4=O)=C([H])/CC1OC5(CCC(C)C(C(C)C)O5)CC(O4)C1

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H

OO H

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Complex RingAnalysis

• Not really a norbornane-type bridge system• 3 trans-ringbonds• 2 implicit cis bonds• 2 implicit trans bonds

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O HH H

H


The CACTVS Plot Algorithms

• Defines state of the art• Fully stereo-aware, in chains and rings• Triple bonds in rings• Automatic wedge assignment• Intelligent pseudo-energy optimizer

C[C@H]1[C@H](C)CC\C=C/[C@H](OC)/C=C/[C@@](C)(O)/C=C/C(O1)=O


Open Access

Test it!

http://www2.ccc.uni-erlangen.de/services/gif.html (final version soon)


Not just a Passive Image...

Web Interface

With image maps:

Portable,

user-friendly

selection/

manipulation

alternative

C[C@H]1[C@H](C)CC\C=C/[C@H](OC)/C=C/[C@@](C)(O)/C=C/C(O1)=O


More Examples

OO

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S

OH

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H

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NH

ON

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O N

OO

N O

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Topics

• Motivation





Just a typicalsmall screening

experiment

1148structures


346 Clusters

cluster #19218 compounds

fingerprintclustering(144 bits)


A Closer Look

• Plots have similar characteristics• Structures not optimally aligned


Aligning Multiple Structures

• Move Morgan-center atom to origin• Operate on hexagonal grid• Center on grid

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Operations on structures:

• Move to neighbor grid (6)

• Rotate by multiple of 60 degs. (5)• Rotation around center or hetero atom• Horizontal and vertical flip• 120 deg. flip of non-terminal, non-ringbond• Shuffle to other sequence position



Merit function:• Multiple occupation of grid cells• Bonus for overlay of ring atoms, aromatic atoms, hetero atoms• Multiplicative rating within cell• Rate only against earlier entries in sequence, weight 1/n

Optimizer:• Taboo-search


A Simple Example

S

H N

HN

S

OH N

NH

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SO H N

NH


TheCleaned Cluster


Topics

• Motivation





Atomic Charges - Wild Growth...


More Methods to Display Charges...


And Another Method!


2D Voronoi Polygons

• Polygons around atoms• Full use of available space• Extra hidden points to limit area• Encode attribute by color codes• Immediate recognition


Back to the Cluster

• David Covell, NCI, NIH: „What is the essence? How can I SEE what the principle behind the cluster is?“

• What are the similarities?• What are the differences?• What is the prototypical compound?


Decoding Fingerprints

• Fingerprints encode presence of fragments• No count• No location

• Vector %11010

• Loss of information - can it be reclaimed or ignored?

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Decoding Fingerprints

Approach: • Perform statistics on all possible matches of all fragments in fingerprint set and weigh atom participation

• Relative occurence of fragments on atom compared to prototype

• Prototype is either virtual average cluster structure, or specific selected compound


Results:VirtualMedian Structure


Results: Chose aPrototype


Results: ChoseAnotherPrototype


Acknowledgements

• Marc Nicklaus, David Covell, et al. at NCI, NIH

• BASF

• Chemical Concepts

• DuPont de Nemours


More Information

W. D. Ihlenfeldt

[email protected]

http://www2.ccc.uni-erlangen.de/wdi/

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