1 Szabolcs Csepregi*, Szilárd Dóránt, Nóra Máté, Miklós Vargyas, Péter Kovács, György Pirok, Ferenc Csizmadia January, 2007 Structural Search Using ChemAxon Tools

Slide 2 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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 plans All examples were generated by Marvin

Slide 3 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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

Slide 4 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version ChemAxon Products Overview

Slide 5 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Selected Application Areas Global licenses Custom development projects Value added constructions Websites/portal front and back end Content/ Educational

Slide 6 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version For academic teaching and research More information at: 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

Slide 7 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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)

Slide 8 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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

Slide 9 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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

Slide 10 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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.

Slide 11 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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 00,000s+ 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

Slide 12 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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

Slide 13 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version JChem Cartridge for Oracle

Slide 14 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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

Slide 15 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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

Slide 16 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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):

Slide 17 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Query features 2. Query properties Query properties: SymbolDescription H Total hydrogen count aAromatic AAliphatic R Ring count in SSSR r Ring size in SSSR v Valence X Connectivity D Degree h Implicit H count rb rb*Ring bond count *: as drawn s s*Substitution count *: as drawn uUnsaturated atom

Slide 18 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Query features 3. Atomic SMARTS features SMARTS atoms: Additional query properties: Example: Carbonyl C, but not amide SymbolDescription & ;, !Logical operators $( )Recursive smarts +0, -0Zero charge

Slide 19 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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 SymbolDescription - = #Single, double, triple :aromatic &, ; !Logical bond / \ /? \?Directional bond (cis/trans) SymbolDescription (C.C)Same component (C).(C)Different component C.CNo component restrictions

Slide 20 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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

Slide 21 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Stereo searching 2. Tetrahedral chirality Stereo bond types: Relative stereo configuration Chiral flag model Enhanced stereo representation: AND, OR, ABS groups Up or downDownUp

Slide 22 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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:

Slide 23 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Reaction search Reactants, agents, products Transformation recognition (mapping) Stereospecific reactions (inversion, retention) Reactant grouping Reacting center

Slide 24 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version R-group search Scaffold, R-group definitions Monovalent, divalent R-groups R-logic Occurrence If-then Rest H

Slide 25 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Hydrogens H representations: – Explicit – Implicit – Query H count: – total (H ) – implicit (h ) Example: Considered in ABAS Explicit HImplicit HQuery H count Query Target Query

Slide 26 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Applications of Chemical Terms CT virtual synthesis reaction and synthesis rules pharmacophore analysis pharmacophore definitions drug design goal functions structural search advanced query expressions e.g. in Instant JChem & Cartridge

Slide 27 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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

Slide 28 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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.

Slide 29 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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 Fingerprint screening Need to be searched Screened out Atom by atom search Results

Slide 30 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Performance Searching 3 million smiles structures (multiplied NCI 2000) in DB: JChem Base 3.2, Dual Xeon 3GHz, 2GB RAM; Oracle QueryNumber of hitsSearch time (s)

Slide 31 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Demo

Slide 32 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Application: R-group decomposition JChem is able to identify the ligands of a given scaffold at specified substitution positions: Query(scaffold) Result Library R-group decomposition

Slide 33 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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:

Slide 34 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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.)

Slide 35 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version 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 2 63 members Atom lists Bond lists Link nodes

Slide 36 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Summary JChem suite: contains a broad range of chemical search facilities. Chemical Terms: allows easy and flexible data mining. Structural search is a useful tool for many applications.

Slide 37 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version References JChem Query Guide: Chemical Terms reference: JChem Base JSP demo page: Instant JChem: Jcsearch command line tool: API documentation: (chemaxon.sss.search.MolSearch, chemaxon.jchem.db.JChemSearch)chemaxon.sss.search.MolSearchchemaxon.jchem.db.JChemSearch

Slide 38 Structural Search Using ChemAxon Tools ICCI Pune India, January 2007 JChem version Máramaros köz 3/a Budapest, 1037 Hungary Thank you for your attention