Slide 1 Structural Search Using ChemAxon Tools JChem version 5.3 Structural Search Using ChemAxon...

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Structural Search Using ChemAxon Tools — JChem version 5.3

Structural Search Using ChemAxon Tools

Szabolcs Csepregi

1JChem version 5.3, April 2010

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Structural Search Using ChemAxon Tools

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Interfaces

Search types and options

Query features, Stereo searching

Special search types: reaction, R-group search, Chemical Terms filters

Searching against Combinatorial Markush structures

Fingerprint screening

Performance

Applications of structural search: R-group decomposition, Standardizer, Reactor, Pmapper, Fragmenter

Future plans

All examples were generated by Marvin

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Structural search interfaces

• Example web GUI-s:– JSP (Java Server Pages)

– AJAX example: Javascript and

JChem Web Services

• Command line: jcsearch

• Java and .NET API: –MolSearch class:

in memory

–JChemSearch class: in database

• Cartridge: Oracle SQL

• JChem Web Services

• Instant JChem

• JChem For Excel

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Search types in JChem

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• Atom By Atom Search or structural search:

• Similarity search:– Different Descriptors– Different Metrics

MC(E)S – maximum common (edge) substructure

Duplicate

Full structure

Superstructure

Substructure

ResultQueryStructural search type

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Some selected structure search options:

• Stereo on/off/diastereomers

• Ignore charge/isotope/radical/valence/polymers, etc.

• Vague bond matching options

• Chemical Terms filter

• Tautomer search (even in substructure search)

• Inverse hit list

• Maximum search time / number of hits

• Combine with non-structure conditions

• Ordering of results

• Similarity type / metric

Search options

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Hit coloring and alignment

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Query features 1. Atomic features

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• Query atom types:

• any(A, AH)

• hetero (Q, QH)

• list, not list

• metal (M, MH)

• halogen (X, XH)

• periodic table groups (G1-18)

• Pseudo atoms e.g. “Resin”

• Explicit lone pairs (match to implied lone pairs as well.)

• Charge, isotope, radical

• Link nodes (repeatable): (L1-2)H3C

(L1-5)

OH

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Query features 2. Query properties

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Symbol Description

H<n> Total hydrogen count

a Aromatic

A Aliphatic

R<n> Ring count in SSSR

r<n> Ring size in SSSR

v<n> Valence

X<n> Connectivity

D<n> Degree

h<n> Implicit H count

rb<n> rb* Ring bond count *: as drawn

s<n> s* Substitution count *: as drawn

u Unsaturated atom

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Query features 3. Atomic SMARTS features

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• SMARTS atoms:

• Additional query properties:

• Example:

Carbonyl C, but not amide

Symbol Description

& ; , ! Logical operators

$(<smarts>) Recursive smarts

+0, -0 Zero charge

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Query features 4. Homology atoms

• Can be used:– In queries against molecule and reaction tables.– In Markush structures

• Built-in and user-defined groups

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Query features 5. Bond features & components

• Query bond types: Any, single or double, single or aromatic, double or aromatic

• Bond topology: chain/ring

• Smarts bonds

• Component level grouping

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Symbol Description

- = # Single, double, triple

: aromatic

& , ; ! Logical operators

@ Ring bond

/ \ /? \? Directional bond (cis/trans)

Symbol Description

(C.C) Same component

(C).(C) Different component

C.C No component restrictions

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Coordination compounds

Atom-to-atom (dative) and multicenter coordinate bonds.

Alternative representations: Positionvariation

bond

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Hydrogens

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• H representations:– Explicit– Implicit– Query H count:

– total (H<n>)

– implicit (h<n>)

• Example:

Considered in ABAS

Explicit H Implicit H Query H count

Query

Target

Target

Query

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Stereo searching 1. Double bonds

• Levels of check:– All– Only marked double bonds

(MDL: stereo care flag)

– None

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Not cis

Not trans

Cis or trans

(unknown)

Trans

Cis

MeaningDepiction

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Stereo searching 2. Tetrahedral chirality

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• Stereo bond types:

• Relative stereo configuration• Chiral flag model• Enhanced stereo representation: AND<n>, OR<n>, ABS groups

Up or downDownUp

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Groups integration (query & target)

Both sides are treated similarly by the search:

• Abbreviations (super-atom S-groups):

• Multiple groups:

Other S-groups supported: component, mixture, formulation , many polymer brackets:

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Reaction search

• Reactants, agents, products

• Transformation recognition (mapping)

• Stereospecific reactions (inversion, retention)

• Reactant grouping

• Reacting center

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R-group search

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• Scaffold, R-group definitions

• Monovalent, divalent R-groups

• R-logic

•Occurrence

•If-then

•Rest H

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Undefined R-atoms

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- No substitution elsewhere

retrieves:

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Polymer storage and search

• Comprehensive representation– Source based and structure based– Copolymer types, mixtures, ladder-type

polymers, etc– Phase shifting– End groups: specific, undefined, etc.

• Flexible– Attached data search– Wide range of polymer search options

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Chemical Terms filter

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Lipinski rule of 5 (mass() <= 500) && (logP() <= 5) && (donorCount() <= 5) &&

(acceptorCount() <= 10);

Veber filter (rotatableBondCount() <= 10) &&

(PSA() <= 140);

• Chemically aware filtering for structure and similarity searches

• Elements of the Chemical Terms language– structure matching functions (describing functional groups, reaction sites, similarity,

etc)– property calculations (partial charge distribution, pKa, logP, HB donors, acceptors,

topological descriptors, etc)– arithmetic and logic-operators

Examples

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Markush structures

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Markush structure registration and search

• Markush features

― R-groups

― Atom lists, bond lists

― Position variation bond

― Link nodes and repeating units

― Homology groups

• Compatible enumeration plugin

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Fingerprint screening in the database

• JChem database searches use fingerprint technology for fastest search results.

• It rapidly* filters out most non-hits -usually more than 99% of them are rejected.

• Supported fingerprint types:– Chemical hashed fingerprints– User-defined additional structural keys

* Average screening time in a 3-million cached table: ~0.1s

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JChem table

Hits for the query

Search

query

Fingerprintscreening

Need to be searched

Screenedout

Atom by atomsearch

Results

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Application: R-group decomposition

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JChem is able to identify the ligands of a given scaffold at specified substitution positions:

Query(scaffold) Result

Library R-groupdecomposition

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Further applications of structural search in JChem

• Transformations - Standardizer & Reactor

• Identification of pharmacophoric groups - Pmapper

nitro: amidine:

• Identification of bond cleavage - Fragmenter

ether cut:

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Enamine-amine tautomerism:

Converting covalent form of alcoholates to ionic form:

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Performance

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Substructure searching in 19.5 million structures (Pubchem)

JChem Base 5.2.2, Intel Quad Q6600 2.4GHz, 8 GB RAM; Oracle 10.2.0.3

Query Number of hits Search time

2 0.91 s

93 0.98 s

6,001 1.30 s

146,256 5,66 s

Number of compounds

Elapsed time

Duplicates not checked

Duplicates checked

10,000 21 s 26 s

100,000 2 min 4 s 2 min 34 s

200,000 4 min 24 s 5 min 13 s

Compound registration:

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Future plans

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• R-group decomposition GUI in client applications

• Visualization of similarity search results using MCS

• Diastereomer search

• Markush search enhancements (homology variation conditions, maximum common substructure, etc)

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Summary

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• JChem suite: contains a broad range of chemicalsearch facilities, including Markush

structure analysis.

• Structural search is a useful tool for many applications.

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References

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• JChem Query Guide http://www.chemaxon.com/jchem/doc/user/Query.html

• Chemical Terms reference http://www.chemaxon.com/jchem/marvin/help/chemicalterms/ChemicalTerms.html

• JChem Base JSP demo page http://www.chemaxon.com/jchem/examples/db_search/index.jsp

• Jcsearch command line tool http://www.chemaxon.com/jchem/doc/user/Jcsearch.html

• API documentation http://www.chemaxon.com/jchem/doc/api/index.html

(chemaxon.sss.search.MolSearch, chemaxon.jchem.db.JChemSearch)

• JChem Base http://www.chemaxon.com/product/jc_base.html

• JChem Cartridge http://www.chemaxon.com/product/jc_cart.html

• Instant JChem http://www.chemaxon.com/product/ijc.html

• JChem for Excel http://www.chemaxon.com/products/jchem-for-excel/

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Structural Search Using ChemAxon Tools — JChem version 5.3 30

Thank you for your attention

Máramaros köz 3/a Budapest, 1037Hungary

[email protected]

www.chemaxon.com

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Slide 1 Structural Search Using ChemAxon Tools JChem version 5.3 Structural Search Using ChemAxon...

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