Chemical Terms, a Language for Cheminformatics

György Pirok

American Chemical Society National Meeting, Chicago 2007

Content

Problems to solve

Property calculations, the plugin system

The Chemical Terms language

Applications

Summary

Problems to Solve

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?

How can we detect activated/deactivated sites, regioselectivity or potential side reactions?

How can chemists improve a virtual reaction if it provides unfeasible products?

Virtual reactions

Problems to Solve

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?

What goal function should we set?

How to define a custom goal function including desired physicochemical properties?

Random evolutionary de Novo drug design

The Chemical Terms Pyramid

Applications

Chemical TermsEvaluator

Plugin System

Property Calculations

Property Calculations

Plugins are Accessible

GUIs

command line tools

Java API

SQL Cartridge

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

Chemical Terms Function ExamplesSubstructure Matching

The query can be specified in file, or can be "inlined":

match("[#6:1][$([NX3:2](=[O:3])=[O:3]),$([NX3+:1](=[O:3])[O-:3])]")

match("nitroquery.mol") // true if the query found in the// current molecule

matchCount(aliphaticamine) // returns the number of aliphatic amino// groups in the current molecule

Counting functional groups:

match(ratom(6), "[OH:1]C=[O:2]", 1, 2) // is the given reactant atom a// carboxyl oxygen?

Matching a mapped atom of the functional group of a reactant in reaction context:

match(nitro) // true if the current molecule contains // nitro group

Built-in dictionaries supporting named functional groups and reactions:

match(BeckmannRearrangement) // true if the current reaction is a// rearrangement of an oxime to amide

Function ExamplesChemical Calculations

Calculating physicochemical properties of the current molecule:

solventAccessibleSurfaceArea("7.4") // on pH 7.4

isoelectricPoint()

acidicpKa(ratom(4)) // the acidic pKa of the given reactant atom

Calculating physicochemical properties in reaction context:

electrophilicLocalizationEnergy(ratom(3))

logP(product(1)) // the logP of the given product

rotatableBondCount()

Calculating topological and geometrical descriptors:

SzegedIndex()

heteroAromaticRingCount()

hasValidConformer(product(1))

stericHindrance(ratom(7))

chiralCenterCount(ratom(7))

Function ExamplesCalculations Returning Molecules

Predicting the major microspecies on the given pH

majorMicrospecies("7.0")

tautomer(1, "7.4") // dominant tautomer on the given pH

Determining resonant structures and tautomers of the current molecule

tautomers() // all tautomers

canonicalResonant() // canonical resonant structure

resonants() // all resonant structures

Returning the stereoisomers of the given product in the current reaction

stereoIsomers(product(1))

Returning all enumerated molecules of a given Markush structure

enumeration()

Combining functions in Chemical Terms

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

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)

acceptorCount(product(1), "7.4")

name of the function

Molecule context Reaction context

acceptorCount("7.4")

name of the function

Chemical Terms Syntax and Context

parameters parameters

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

The Chemical Terms Editor

Applications

The problem

Property calculations, the plugin system

The Chemical Terms Language

ApplicationsSummary

Applications of Chemical Terms Calculated Fields and Filters in Instant JChem

Applications of Chemical Terms Filters in Pipeline Pilot

Applications of Chemical TermsVirtual Reaction without Chemical Terms

Applications of Chemical TermsReaction Editor - Encoding Reaction Rules

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

Applications of Chemical TermsHuman Xenobiotic Biotransformations

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...

Summary

The problem

Property calculations, the plugin system

The Chemical Terms Language

Applications

Summary

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

Acknowledgements

Nóra Máté, Zsolt MohácsiPlugin system, Chemical Terms Evaluator, Reactor, Pharmacophore mapping

József Szegezdi, Ferenc CsizmadiaProperty predictions, calculations

István Cseh, Attila SzabóChemical Terms Editor

Szilárd Dóránt, Szabolcs CsepregiSubstructure searching functions, JChem Base integration, Pipeline Pilot integration

Péter KovácsJChem Cartridge integration

Tim Dudgeon, Petr HamernikInstant JChem Integration

Miklós Vargyas

Pharmacophore mapping, Chemical Terms Evaluator