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Structural Search Using ChemAxon Tools

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1 Structural Search Using ChemAxon Tools
Szabolcs Csepregi JChem version 5.3, April 2010

2 Structural Search Using ChemAxon Tools
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

3 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 JChemBase JSP example: Jcsearch user’s guide: API Documentation: Search classes: chemaxon.jchem.db.JChemSearch Instant JChem JChem For Excel

4 Structural search type
Search types in JChem Structural search type Query Result Atom By Atom Search or structural search: Similarity search: Different Descriptors Different Metrics Substructure Superstructure Full structure Duplicate MC(E)S – maximum common (edge) substructure

5 Search options 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 5

6 Hit coloring and alignment

7 Query features 1. Atomic features
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):

8 Query features 2. 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

9 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

10 Query features 4. Homology atoms
Can be used: In queries against molecule and reaction tables. In Markush structures Built-in and user-defined groups

11 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 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

12 Coordination compounds
Atom-to-atom (dative) and multicenter coordinate bonds Alternative representations: Position variation bond

13 Hydrogens H representations: Example: 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

14 Stereo searching 1. Double bonds
Not cis Not trans Cis or trans (unknown) Trans Cis Meaning Depiction Levels of check: All Only marked double bonds (MDL: stereo care flag) None

15 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 down Down Up

16 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:

17 Reaction search Reactants, agents, products
Transformation recognition (mapping) Stereospecific reactions (inversion, retention) Reactant grouping Reacting center

18 R-group search Scaffold, R-group definitions
Monovalent, divalent R-groups R-logic Occurrence If-then Rest H

19 Undefined R-atoms - No substitution elsewhere retrieves:

20 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

21 Chemical Terms filter 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 Lipinski rule of 5 (mass() <= 500) && (logP() <= 5) && (donorCount() <= 5) && (acceptorCount() <= 10); Veber filter (rotatableBondCount() <= 10) && (PSA() <= 140);

22 Markush structure registration and search
Markush structures 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

23 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 JChem table Hits for the query Search query Fingerprint screening Need to be searched Screened out Atom by atom search Results

24 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

25 Further applications of structural search in JChem
Transformations - Standardizer & Reactor Identification of pharmacophoric groups - Pmapper nitro: amidine: Identification of bond cleavage - Fragmenter ether cut: Converting covalent form of alcoholates to ionic form: Enamine-amine tautomerism:

26 Duplicates not checked
Performance Query Number of hits Search time 2 0.91 s 93 0.98 s 6,001 1.30 s 146,256 5,66 s Substructure searching in 19.5 million structures (Pubchem) JChem Base 5.2.2, Intel Quad Q GHz, 8 GB RAM; Oracle Compound registration: 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

27 Future plans 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)

28 Summary JChem suite: contains a broad range of chemical search facilities, including Markush structure analysis. Structural search is a useful tool for many applications.

29 References JChem Query Guide Chemical Terms reference JChem Base JSP demo page Jcsearch command line tool API documentation (, chemaxon.jchem.db.JChemSearch) JChem Base JChem Cartridge Instant JChem JChem for Excel

30 Thank you for your attention
Máramaros köz 3/a Budapest, 1037 Hungary

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