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Chemical Terms, a Language for Cheminformatics

American Chemical Society. National Meeting, Chicago 2007. Chemical Terms, a Language for Cheminformatics. György Pirok. Content. Problems to solve Property calculations, the plugin system The Chemical Terms language Applications Summary. Virtual reactions.

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Chemical Terms, a Language for Cheminformatics

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  1. American Chemical Society National Meeting, Chicago 2007 Chemical Terms, a Language for Cheminformatics György Pirok

  2. Content Problems to solve Property calculations, the plugin system The Chemical Terms language Applications Summary

  3. Virtual reactions How can we detect activated/deactivated sites, regioselectivity or potential side reactions? How can chemists improve a virtual reaction if it provides unfeasible products? Filtering Thousands of predictive calculations, topological indices, and many "likeness"rules are published. Which ones of them should be supported by our database tools? How could chemists combine these predictions during structure searching? How could chemists use their existing property calculations inside ChemAxon tools? Problems to Solve

  4. Pharmacophore mapping What pharmacophore types should we define? Should we define pharmacophore types using functional group lists or property calculations? How to extend the definitions? Random evolutionary de Novo drug design What goal function should we set? How to define a custom goal function including desired physicochemical properties? Problems to Solve

  5. The Chemical Terms Pyramid

  6. Property Calculations

  7. Plugins are Accessible GUIs SQL Cartridge Java API command line tools

  8. The Plugin System is Extensible acceptor acceptorCount acceptorSiteCount acidicpKa acidicpKaLargeModel aliphaticAtom aliphaticAtomCount aliphaticBondCount aliphaticRingCount angle aromaticAtom aromaticAtomCount aromaticBondCount aromaticElectrophilicityOrder aromaticNucleophilicityOrder aromaticRingCount array asymmetricAtom asymmetricAtomCount atno atomCount atomicPolarizability averagePolarizability balabanIndex basicpKa basicpKaLargeModel BCUT bond bondCount bondType canonicalResonant canonicalTautomer carboaromaticRingCount carboRingCount chainAtom chainAtomCount chainBond chainBondCount charge chiralCenter chiralCenterCount composition conformer conformerCount conformers connected connectedGraph connections count cxsmarts cxsmiles cyclomaticNumber dihedral dissimilarity distance distanceDegree donor donorCount donorSiteCount dotDisconnectedFormula doubleBondStereoisomer doubleBondStereoisomerCount doubleBondStereoisomers dreidingEnergy eccentricity electrophilicLocalizationEnergy enumeration enumerationCount enumerations exactMass field filter formalCharge formula fusedAliphaticRingCount fusedAromaticRingCount fusedRingCount hararyIndex hasValidConformer hydrogenCount heavy heteroaromaticRingCount heteroRingCount hyperWienerIndex isoelectricPoint isotopeComposition isotopeFormula largestAtomRingSize largestRingSize logD logP logPIncrement logS logSMicro logSNeutral logSTrue lowestEnergyConformer majorMicrospecies majorMs map mass match matchCount max maxAtom maxValue microspecies microspeciesCount microspeciesDistribution min minAtom minValue molBinFormat molecularPolarizability molFormat molImage name nucleophilicLocalizationEnergy pair piChargeDensity piEnergy piOrbitalElctronegativity pKa plattIndex polarizability property randicIndex refractivity refractivityIncrements resonant resonantCount resonants ringAtom ringAtomCount ringBond ringBondCount ringCount ringCountOfAtom rotatableBond rotatableBondCount shortestPath sigmaOrbitalElectronegativity smallestAtomRingSize smallestRingSize smarts smiles solventAccessibleSurfaceArea sortAsc sortDesc stereoisomer stereoisomerCount stereoisomers stericEffectIndex stericHindrance sum szegedIndex tautomer tautomerCount tautomers tetrahedralStereoisomer tetrahedralStereoisomerCount tetrahedralStereoisomers topologicalPolarSurfaceArea totalChargeDensity traditionalName uniqueSmiles valence vanDerWaalsSurfaceArea wienerIndex wienerPolarity

  9. The query can be specified in file, or can be "inlined": match("nitroquery.mol")// true if the query found in the // current molecule match("[#6:1][$([NX3:2](=[O:3])=[O:3]),$([NX3+:1](=[O:3])[O-:3])]") Built-in dictionaries supporting named functional groups and reactions: match(nitro)// true if the current molecule contains // nitro group match(BeckmannRearrangement)// true if the current reaction is a // rearrangement of an oxime to amide Counting functional groups: matchCount(aliphaticamine)// returns the number of aliphatic amino // groups in the current molecule Matching a mapped atomof the functional group of a reactant in reaction context: match(ratom(6),"[OH:1]C=[O:2]", 1, 2) // is the given reactant atom a // carboxyl oxygen? Chemical Terms Function ExamplesSubstructure Matching

  10. Calculating physicochemical properties of the current molecule: isoelectricPoint() solventAccessibleSurfaceArea("7.4")// on pH 7.4 Calculating physicochemical properties in reaction context: acidicpKa(ratom(4))// the acidic pKa of the given reactant atom electrophilicLocalizationEnergy(ratom(3)) logP(product(1))// the logP of the given product Calculatingtopological and geometrical descriptors: rotatableBondCount() SzegedIndex() heteroAromaticRingCount() hasValidConformer(product(1)) stericHindrance(ratom(7)) chiralCenterCount(ratom(7)) Function ExamplesChemical Calculations

  11. Predicting the major microspecies on the given pH majorMicrospecies("7.0") Determining resonant structures and tautomers of the current molecule resonants()// all resonant structures canonicalResonant()// canonical resonant structure tautomers()// all tautomers tautomer(1, "7.4")// dominant tautomer on the given pH Returning the stereoisomers of the given product in the current reaction stereoIsomers(product(1)) Returning all enumerated molecules of a given Markush structure enumeration() Function ExamplesCalculations Returning Molecules

  12. Creating complex descriptors for filtering: (mass() >= 200) && (mass() <= 600) && (ringCount() <= 7) && (atomCount("6") >= 5) && ((atomCount() - atomCount("6") - atomCount("1")) >= 2) && (rotatableBondCount() <= 15) && (donorCount() <= 5) && (acceptorCount() <= 10) && (logP() >= -2) && (logP() <= 5) && (polarSurfaceArea() <= 150); Defining goal functions for random evolutionary drug design applications: inhibitor=inhibitor.mol; dissimilarity(inhibitor, pharmacophore_tanimoto) - dissimilarity(inhibitor,chemical_tanimoto); Pharmacophore type definition (cationic): (formalcharge() > 0) || (charge("7.4") > 0.4) Combining functions in Chemical Terms

  13. Identifying deactivated rings in virtual Friedel-Crafts acylation: charge(ratom(1), "aromaticsystem") > -0.2 Determining the localization energy effect on regioselectivity in SEAr reactions: electrophilicLocalizationEnergy (ratom(1)) Excluding reactants having sensitive groups in Friedel-Crafts acylation: match(reactant(1),"[Cl,Br,I]C(=[O,S])C=C") || match(reactant(0), "[H][O,S]C=[O,S]") || match(reactant(0),"[P][H]") || (max(pka(reactant(0), filter(reactant(0), "match('[O,S;H1]')"),"acidic")) > 14.5) ||(max(pka(reactant(0), filter(reactant(0), "match('[#7:1][H]',1)"), "basic")) > 0) Combining functions in Chemical Terms

  14. Chemical Terms Syntax and Context acceptorCount("7.4") acceptorCount(product(1), "7.4") parameters name of the function parameters name of the function Parameters: molecule, atom, other custom parameters (e.g. pH) • Molecule context, used for single molecule input • mol(): refers to the current input molecule (can be omitted) • Reaction context, used for reaction input initiated by the Reactor: • reactant(int i): refers to the i-th reactant (0-based indexing) • product(int i): refers to the i-th product (0-based indexing) • ratom(int m): refers to the reactant atom corresponding to reactant atom map m according to the reaction equation • patom(int m): refers to the product atom corresponding to product atom map m according to the reaction equation Additional contexts: atom context, search context

  15. The Chemical Terms Editor

  16. Applications The problem Property calculations, the plugin system The Chemical Terms Language Applications Summary

  17. Applications of Chemical TermsCalculated Fields and Filters in Instant JChem

  18. Applications of Chemical TermsFilters in Pipeline Pilot

  19. Applications of Chemical TermsVirtual Reaction without Chemical Terms

  20. Applications of Chemical TermsReaction Editor - Encoding Reaction Rules

  21. Applications of Chemical TermsVirtual Reaction with Chemical Terms György Pirok, Nóra Máté, Jenő Varga, József Szegezdi, Miklós Vargyas, Szilárd Dóránt, and Ferenc Csizmadia: Making "Real" Molecules in Virtual Space. J. Chem. Inf. Model.; 2006; 46(2) pp 563 - 568

  22. Applications of Chemical TermsHuman Xenobiotic Biotransformations

  23. Upcoming Features • simplified syntax • replacing &&, ||, ! with and, or, not • numbering base will be 1 universally • strongly typed parameters • simplified editing • syntax checker in editor • parameter dialogs in editor • more named functional groups in the dictionary • named reaction dictionary • new functionalities • functional group transformation queries in matching (carboxyl>>aldehide) • referring to database fields • conditional expressions (if) • IUPAC name functions • and more...

  24. Summary The problem Property calculations, the plugin system The Chemical Terms Language Applications Summary

  25. Summary • What is Chemical Terms? • A simple but extensible language to combine chemical functions for various cheminformatics purposes • A way to add more chemical "intelligence" to software programs • A general interface for chemists to customize cheminformatics applications • What is it good for? • chemical data filtering • creating complex SAR expressions • making virtual reactions, biotransformations selective • defining goal functions, termination criterias • defining pharmacophore types • and more... • How can I use it? • Off the shelf (Reactor, Metabolizer, Instant JChem, command line) • Integrate into own applications (Java/.NET API, Oracle Cartidge) • FREE for Academics

  26. Acknowledgements Nóra Máté, Zsolt Mohácsi Plugin system, Chemical Terms Evaluator, Reactor, Pharmacophore mapping József Szegezdi, Ferenc Csizmadia Property predictions, calculations István Cseh, Attila Szabó Chemical Terms Editor Szilárd Dóránt, Szabolcs Csepregi Substructure searching functions, JChem Base integration, Pipeline Pilot integration Péter Kovács JChem Cartridge integration Tim Dudgeon, Petr Hamernik Instant JChem Integration Miklós Vargyas Pharmacophore mapping,Chemical Terms Evaluator

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