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Virtual Synthesis

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Virtual Synthesis - Reactor

Elements of the Virtual Synthesis Technology
• Chemical properties predictions
– Calculator Plugins

• A language for describing chemical rules
– Chemical Terms

• A library of selective reactions „knowing” chemistry
– Chemaxon Reaction Library

• A reaction engine with high capacity and performance
– Reactor

• Virtual synthesis applications
– Synthesizer (combinatorial, random, exhaustive)

Chemical Terms, a Language for Cheminformatics
Elements of the language
• • • structure matching functions (describing functional groups, reaction sites, similarity…) property calculations (partial charge distribution, pKa, logP, localization energy…) arithmetic and logic-operators

Chemical Terms examples
structure search goal function
match("olefine.mol") and !match("c1ccncc1") and (atomCount("16") == 0) or (mass() < 300); inhibitor = inhibitor.mol; similarity(inhibitor, chemical_tanimoto) - similarity(inhibitor, pharmacophore_tanimoto);

drug likeness filter

(mass() <= 500) and (logP() <= 5) and (donorCount() <= 5) and (acceptorCount() <= 10);

Calculator Plugins
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 solubility solubilityAtIsoelectricPoint solubilityOfMicroSpecies solubilityOfNeutral solventAccessibleSurfaceArea sortAsc sortDesc stereoisomer stereoisomerCount stereoisomers stericEffectIndex stericHindrance sum szegedIndex tautomer tautomerCount tautomers tetrahedralStereoisomer tetrahedralStereoisomerCount tetrahedralStereoisomers topologicalPolarSurfaceArea totalChargeDensity traditionalName uniqueSmiles valence vanDerWaalsSurfaceArea wienerIndex wienerPolarity

Applications of Chemical Terms
virtual synthesis
reaction and synthesis rules

pharmacophore analysis
pharmacophore definitions

CT
structure searching

drug design
goal functions

advanced query expressions

Encoding Synthetic Knowledge in Reactions
The Friedel-Crafts acylation

Charles Friedel 1832-1899

James Mason Crafts 1839-1917

Encoding Synthetic Knowledge in Reactions
The Friedel-Crafts acylation: generic scheme

The hydrogen of an aromatic carbon atom is substituted with an acyl group of an acid halide during hydrogen halide elimination.
C(a) L[O, S] L[Cl, Br, I] aromatic carbon atom oxygen or sulfur atom chlorine, bromine or iodine atom

Encoding Synthetic Knowledge in Reactions
The Friedel-Crafts acylation: finding reactive sites

REACTIVITY:

charge(ratom(1), "aromaticsystem") < -0.2

Friedel-Crafts acylation occurs only if the aromatic system is at least as activated as monohalobenzenes.

Encoding Synthetic Knowledge in Reactions
The Friedel-Crafts acylation: finding the most reactive sites

SELECTIVITY: TOLERANCE:

-energyE(ratom(1)) 0.02

Directing rule: the electrophilic substitution takes place on the aromatic carbon atom with the lowest localization energy having an attached electrophile in the transition state. Aromatic carbons having the lowest localization energies provide the main product. Aromatic carbons having similar localization energies to the lowest one (within 0.02 tolerance range) are included.

Encoding Synthetic Knowledge in Reactions
The Friedel-Crafts acylation: excluding compounds giving side reactions, destroying the catalyst

EXCLUDE:

match(reactant(1), "[Cl,Br,I]C(=[O,S])C=C") or match(reactant(0), "[H][O,S]C=[O,S]") or match(reactant(0), "[P][H]") or (max(pka(reactant(0), filter(reactant(0), "match('[O,S;H1]')"), "acidic")) > 14.5) or (max(pka(reactant(0), filter(reactant(0), "match('[#7:1][H]', 1)"), "basic")) > 0)

Exclude aromatic compounds containing nucleophilic groups and acrylic halides. For example, phenols and indols are processed, but benzylalcohols or anilines are not.

Encoding Synthetic Knowledge in Reactions
The Friedel-Crafts acylation as a smart reaction

REACTIVITY: SELECTIVITY: TOLERANCE: EXCLUDE:

charge(ratom(1), "aromaticsystem") < -0.2 -energyE(ratom(1)) 0.02 match(reactant(1), "[Cl,Br,I]C(=[O,S])C=C") or match(reactant(0), "[H][O,S]C=[O,S]") or match(reactant(0), "[P][H]") or (max(pka(reactant(0), filter(reactant(0), "match('[O,S;H1]')"), "acidic")) > 14.5) or (max(pka(reactant(0), filter(reactant(0), "match('[#7:1][H]', 1)"), "basic")) > 0

Reactor, the engine
ChemAxon Reaction Library
Baeyer-Villiger ketone oxidation Baylis-Hillman vinyl alkylation Beckmann rearrangement Bischler-Napieralski isoquinoline synthesis Friedel-Crafts reaction Friedlander quinoline synthesis Gabriel synthesis Grignard reaction Hell-Volhardt-Zelinski halogenation

Reactants

Products

REACTOR

Reactor the Application

The Reaction Editor

Reactor, key features
Effective
– – – – – – – – – millions of compounds in a combinatorial reaction up to 500,000 compounds / hour (P4 1.8 GHz) reactions: MRV, RXN, RDF, SMARTS/SMIRKS compounds: MRV, MOL, SDF, SMILES mapping: MDL, Daylight, automapper memory, file and database operations (via Oracle Cartridge) sequential or combinatorial mode compound or reaction output type reverse direction chemo-, regio- and stereospecific customizable Java API, command line tool, JSP, GUI premade reaction library documentation and examples free for the Academic community

Compatible

Flexible

Smart
– – – – – –

Available

Visit other technical presentations
MarvinSketch/View MarvinSpace Calculator Plugins JChem Base JChem Cartridge Standardizer Screen JKlustor Fragmenter Reactor
http://www.chemaxon.com/MarvinSketch_View.ppt http://www.chemaxon.com/MarvinSpace.ppt http://www.chemaxon.com/Calculator_Plugins.ppt http://www.chemaxon.com/JChem_Base.ppt http://www.chemaxon.com/JChem_Cartridge.ppt http://www.chemaxon.com/Standardizer.ppt http://www.chemaxon.com/Screen.ppt http://www.chemaxon.com/JKlustor.ppt http://www.chemaxon.com/Fragmenter.ppt http://www.chemaxon.com/Reactor.ppt


				
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