1 Szabolcs Csepregi May, 2005 Structural Search Using ChemAxon Tools.

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Szabolcs Csepregi

May, 2005

Structural Search Using ChemAxon Tools

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Structural Search Using ChemAxon Tools — May 2005

Structural Search Using ChemAxon Tools

Search types in JChem

Interfaces

Search optionsSearch query features

Stereo searching

The Chemical Terms language

Performance

Applications of structural search:R-group decomposition

Standardizer, Reactor, Pmapper, Fragmenter

Future plans

All examples were generated by Marvin

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Search types in JChem

• Atom By Atom Search or structural search:

• Similarity search:– Different Descriptors– Different Metrics

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

Perfect

Exact

Superstructure

Substructure

ResultQueryStructural search type

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Structural search interfaces

• JSP(Java Server Pages): web GUI for database

• Command line utility: jcsearch: for files and DB

• Java API: – MolSearch class

• isMatching() – Only to check matching

• findFirst(), findNext()Enumerate all

• findAll() possible matchings

– JChemSearch class: JChem Base

• Cartridge: access all functionality from SQL

• Chemical Terms

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ABAS options

• Structural search options:

• Order sensitive hits e.g.• Pre-assignment of query and target atoms• Consider stereo or not, absolute stereo (ignore chiral flag)• Timeout limit• Exact charge/radical/isotope/query features/bond/stereo matching• Double bond stereo: no check/marked/all double bonds• Chemical Terms filter expression• etc

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Query features 1. Atomic features

• Query atom types:

• any,

• hetero,

• list,

• not list

• Pseudo atoms e.g. “Resin”

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

• Charge, isotope, radical

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Query features 2. Query properties

•Query properties:

•Coming soon in search (Can be drawn in Marvin already):•Ring bond count: rb<n>, rb*

•Substitution count: s<n>, s*

•Unsaturated atom: u

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

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Query features 3. Atomic SMARTS features

• 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. 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

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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Stereo searching 1. Double bonds

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

(MDL: stereo care flag)

– None

Not cis

Not trans

Cis or trans

(unknown)

Trans

Cis

MeaningDepiction

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Stereo searching 2. Tetrahedral chirality

• 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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S-group integration (query & target)

Both sides are treated similarly by the search:

• Abbreviations (super-atom S-groups):

• Multiple groups:

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Reaction search

• Reactants, agents, products

• Transformation recognition (mapping)

• Stereospecific reactions (inversion, retention)

• Reactant grouping

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R-group search

• Scaffold, R-group definitions

• Monovalent, divalent R-groups

• R-logic

•Occurrence

•If-then

•Rest H

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Hydrogens

• 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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Applications of Chemical Terms

CT

virtual synthesisreaction and synthesis rules

pharmacophore analysispharmacophore definitions

drug designgoal functions

structural searchadvanced query expressions

e.g. in the Cartridge

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Chemical Terms

searching match("olefine.mol") && !match("c1ccncc1") && (atomCount(16) == 0) || (mass() < 300);

goal functions inhibitor = inhibitor.mol;

(similarity(inhibitor, pharmacophore_tanimoto) > 0.8) && (similarity(inhibitor, chemical_tanimoto) < 0.5);

filtering (mass() <= 500) &&

(logP() <= 5) &&

(donorCount() <= 5) &&

(acceptorCount() <= 10);

• structure matching functions (describing functional groups, reaction sites, similarity…)

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

• arithmetic and logic-operators

Elements of the language

Chemical Terms examples

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Chemical Terms

Some available functions

• Structural search (match, matchcount)• Partial charge distribution • pKa, Log P, Log D, major microspecies• Polarizability• Topological Polar Surface Area• Number of rotatable bonds, rings, aromatic rings, etc.• Number of HB donors/acceptors• Exact mass • Arithmetic and logic operators • Extensible: your own Java plugins can be easily added.• Etc.

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Performance

Searching a file containing 100,000 smiles structures from NCI 99 with the jcsearch command-line application(JChem 3.0.9, P4 2.6GHz, 768M RAM)

Query HitsSearch Time (s)

Total (elapsed, including IO & aromatization)

Search only (measured from API)

1 24.2 0.6

46 26.7 1.8

45,821 65.6 5.4

CCOC(=O)C1=CN=C2C(C)=C(Cl)C=CC2=C1ONC1=CC2=C(C=C1)C(=O)C3=C(C=CC=C3)C2=OCC1=CC=CC=C1

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Application: R-group decomposition

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:

Enamine-amine tautomerism:

Converting covalent form of alcoholates to ionic form:

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Future plans

• More query features (e.g link nodes, ring bond count, substitution count, unsaturated atom)

• Flexible search options: tautomeric search, ignore bond types, salts, etc.

• Search targets having R-groups (Markush structures)

• etc.

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Summary

• JChem suite: contains a broad range of chemicalsearch facilities.

• Chemical Terms: allows easy and flexible data mining.

• Structural search is a useful tool for many applications.

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References

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

• Chemical Terms reference:http://www.jchem.com/doc/user/EvaluatorLanguage.html

• JChem Base JSP demo page:http://www.jchem.com/examples/jsp1_x/index.jsp

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

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

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

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