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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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Structural Search Using ChemAxon Tools — May 2005
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 Using ChemAxon Tools — May 2005
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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Structural Search Using ChemAxon Tools — May 2005
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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Structural Search Using ChemAxon Tools — May 2005
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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Structural Search Using ChemAxon Tools — May 2005
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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Structural Search Using ChemAxon Tools — May 2005
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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Structural Search Using ChemAxon Tools — May 2005
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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Structural Search Using ChemAxon Tools — May 2005
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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Structural Search Using ChemAxon Tools — May 2005
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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Structural Search Using ChemAxon Tools — May 2005
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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Structural Search Using ChemAxon Tools — May 2005
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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Structural Search Using ChemAxon Tools — May 2005
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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Structural Search Using ChemAxon Tools — May 2005
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www.chemaxon.com
Thank you for your attention
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