1 Szabolcs Csepregi*, Szilárd Dóránt, Nóra Máté, Miklós Vargyas, Péter Kovács, György...

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Szabolcs Csepregi*, Szilárd Dóránt, Nóra Máté, Miklós Vargyas, Péter Kovács, György Pirok, Ferenc Csizmadia

January, 2007

Structural Search Using ChemAxon Tools

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Structural Search Using ChemAxon Tools — ICCI Pune India, January 2007 — JChem version 3.2

Structural Search Using ChemAxon Tools

Introduction

Search types in JChem

Interfaces

Search options and features

The Chemical Terms language (search result filtering)

Performance

Applications

Future plansAll examples were generated by Marvin

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ChemAxon introduction

Company

• Founded in 1998, based in Budapest, Hungary, representation in the US, UK and Japan

• Wide cheminformatics expertise (>30 staff) 9 PhD, 11 MSc

• Wide industry expertise >180 corporate clients worldwide + >1000 academic users

Products

• Cheminformatics tools - structure drawing, visualization, search, transformation, library profiling and property prediction

• Enterprise chemistry database and cartridge technology

Technology

• Powerful/Flexible – Enterprise API toolkits

• Solutions – Desktop applications

• Java based + .NET – Platform independent + Web ready

Mantra

• Do what they want, respond quickly

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ChemAxon Products Overview

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Selected Application Areas

Global licenses

Custom development projects

Value added constructions

Websites/portal front and back end

Content/ Educational

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For academic teaching and research

More information at: http://www.chemaxon.hu/forum/ftopic193.html

• Unlimited* personal license for

all products, support and upgrades *JChem base = 3 searches/min

• Open term license for teaching

• Repeating 2 year license term for research – provided ChemAxon are

cited in publications

• License covers students of the department

• Unlimited number of applications / institution

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Where chemical searching useful?

Diversity of applications. :– Compound registration systems– Electronic Laboratory Notebook (ELN) systems – Pharmacophoric group(functional group) identification

(JChem Screen, JKlustor)– Rule-based fragmentation of libraries (JChem

Fragmenter, RECAP)– Virtual reaction processing (JChem Reactor)– Standardization (canonicalization of structures,

JChem Standardizer)– Toxical fragment identification (superstructure search)

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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 and .NET API: – MolSearch class

• isMatching() – Only to check matching

• findFirst(), findNext() Enumerate all• findAll() possible

matchings

– JChemSearch class: JChem Base

• Cartridge: access all functionality from Oracle SQL

• Chemical Terms

• Instant JChem

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Compatibility and integration

File formats:• SMILES• MDL molfile (v2000 and v3000)• MDL SDF• RXN• RDF• MRV

Integration:• 100% Java • extensive API• JChem Cartridge for Oracle• .NET support via JNBridge

Database engines:• Oracle• MySQL• MS SQL Server• PostgreSQL• MS Access• IBM DB2• etc.

Operating systems:• Windows• Linux• Mac OS X• Solaris• etc.

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Instant JChem

Desktop application for local and remote chemical database management, search and structure based prediction

•Simple connect to external databases and share your native database simultaneously

•Powerful search functionalities

•Scalable – explore ’00,000’s+ live structures

•Dynamically predict properties using Calculator Plugins

•Apply canonicalization rules for import and viewing

•Wide import / export options

•Merge data sets into a single set

•Very active development – what do you want to do?

Instant JChem http://www.chemaxon.com/conf/Instant_JChem.ppt

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JChem Cartridge for Oracle

• Access JChem functionalities from non-Java environments via

SQL functions of Oracle

• All search features of JChem Base

• Complex chemical filters and property predictors using

Chemical Terms expressions

• Standardization (structure canonicalization) during registration

• Structure format conversions

• 2D, 3D image generation

• Library enumeration using virtual reactions (Reactor)

JChem Cartridge http://www.chemaxon.com/JChem_Cartridge.ppt

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JChem Cartridge for Oracle

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Canonicalization with Standardizer

• Aromatize/dearomatize

• Add/remove explicit hydrogens

• Convert mesomers / tautomers / functional groups

• Remove solvents counterions by list smallest fragment retain largest fragment

• Set/Remove chiral flag, remove stereo features

• Ungroup S groups

• Enumerate by stoichiometry values

• 2D, 3D coordinate generation (cleaning)

• Template based cleaning

Standardizer http://www.chemaxon.com/Standardizer.ppt

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Search options

Structural search options:

• Stereo on/off, absolute stereo (ignore chiral flag) • Double bond stereo: no check/marked/all double bonds• Chemical Terms filter expression• Tautomer search• Ignore charge/isotope/radical/valence/mixture brackets• Exact charge/radical/isotope/query features/bond/stereo matching• Vague bond matching modes: „or aromatic”; ignore bond types• Timeout limit• Order sensitive hits• Pre-assignment of query and target atoms• 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

• Link nodes (repeatable):(L1-2)

Cl(L1-5)

OH

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Query features 2. Query properties

•Query properties:

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

• 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:

Other S-groups supported: component, mixture and formulation 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

• 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 Instant JChem & 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);

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

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

• 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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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: ~0.5s

JChem table

Hits for the query

Search

query

Fingerprintscreening

Need to be searched

Screenedout

Atom by atomsearch

Results

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Performance

Searching 3 million smiles structures (multiplied NCI 2000) in DB: JChem Base 3.2, Dual Xeon 3GHz, 2GB RAM; Oracle 9.2.0.7.0

Query Number of hits Search time (s)

12 0.5

936 0.7

4608 1.4

65208 11.4

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Demo

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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

• Searching in Markush targets (R-groups, atom lists, link nodes, bond lists)

• New bracket types

• Further generic atom types (AH, QH, X, M, etc.)

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Future plans – Combinatorial Markush database prototype

Stage I. “Combinatorial libraries”Markush features:• R-groups

– Any nesting– Up to 2 connections– In ring or chain

Functionality:• Registration into database

• Search in Markush DB (w/o enumeration)

• Enumeration (full, selective or hit enumeration)

• Enhanced Markush sketching (MarvinSketch)

Very complex Markush libraries can be handled, even ones with more than 263 members

• Atom lists

• Bond lists

• Link nodes

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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

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

• 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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Máramaros köz 3/a Budapest, 1037Hungary

[email protected]

www.chemaxon.com

Thank you for your attention

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1 Szabolcs Csepregi*, Szilárd Dóránt, Nóra Máté, Miklós Vargyas, Péter Kovács, György...

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