In Silico SynthesisGyörgy Pirok, Nóra Máté

Elements of the Virtual Synthesis Technology

• 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)

– Retrosynthesizer

Chemical Terms, a Language for Cheminformatics

structure search match("olefine.mol") && !match("c1ccncc1") && (atomCount(16) == 0) || (mass() < 300);

goal function inhibitor = inhibitor.mol;

similarity(inhibitor, chemical_tanimoto) - similarity(inhibitor, pharmacophore_tanimoto);

drug likeness filter (mass() <= 500) &&

(logP() <= 5) &&

(donorCount() <= 5) &&

(acceptorCount() <= 10);

• structure matching functions (describing functional groups, reaction sites, similarity…)

• property calculations (partial charge distribution, pKa, logP, localization energy…)

• arithmetic and logic-operators

Elements of the language

Chemical Terms examples

Encoding Synthetic Knowledge in ReactionsFriedel-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) aromatic carbon atom

L[O, S] oxygen or sulfur atom

L[Cl, Br, I] chlorine, bromine or iodine atom

Encoding Synthetic Knowledge in ReactionsFriedel-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 mono-halobenzenes.

Encoding Synthetic Knowledge in ReactionsFriedel-Crafts acylation: finding the most reactive sites

SELECTIVITY: -energyE(ratom(1))

TOLERANCE: 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 carbon with the lowest localization energy provides the main product.

Other aromatic carbons having similar localization energies (with less difference than 0.02) are also considered to lead to main products.

Encoding Synthetic Knowledge in ReactionsFriedel-Crafts acylation: excluding compounds giving side

reactions, destroying the catalyst

EXCLUDE: match(ratom(2), "[C:1]C=C", 1) ||match(reactant(0), "[#15][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)

Exclude aromatic compounds containing nucleophilic groups (but do not exclude phenols) and also exclude acrylic halides.

Encoding Synthetic Knowledge in ReactionsFriedel-Crafts acylation as a smart reaction

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

SELECTIVITY: -energyE(ratom(1))

TOLERANCE: 0.02

EXCLUDE: match(ratom(2), "[C:1]C=C", 1) ||match(reactant(0), "[#15][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)

Reactor, the engine

Reactants

REACTOR

ChemAxon Reaction Library

Baeyer-Villiger ketone oxidationBaylis-Hillman vinyl alkylationBeckmann rearrangementBischler-Napieralski isoquinoline synthesisFriedel-Crafts reactionFriedlander quinoline synthesisGabriel synthesisGrignard reactionHell-Volhardt-Zelinski halogenation

Products

Reactor, key features

Effective– millions of compounds in a combinatorial reaction– up to 500,000 compounds / hour (P4 1.8 GHz)

Compatible– reactions: MRV, RXN, RDF, SMARTS/SMIRKS– compounds: MRV, MOL, SDF, SMILES– mapping: MDL, Daylight, automapper

Flexible– memory, file and database operations (even via Oracle Cartridge)– sequential or combinatorial mode– compound or reaction output type– reverse direction

Smart– chemo-, regio- and stereospecific– customizable

Available– Java API, command line tool, JSP– built-in reaction library– documentation and examples– free for the Academic community

Real Combinatorial Synthesis

Derek S. Tan, Michael A. Foley, Matthew D. Shair, Stuart L. Schreiber*, J. Am. Chem. Soc., 1998, 120, 8565-8566

lacton aminolysisalkyne coupling

esterification

Virtual Combinatorial Synthesis

540,600 compunds in the three steps in 2.5 hours (P4 3.0 GHz, Oracle 10g)

Building a Diverse Compound Space

1. 2. 3.

4. 5 6.

Reactor API – part I.

1. Create a Reactor object:

Reactor reactor = new Reactor();

2. Set standardization (optional):

reactor.setStandardizer(standardizer);

reactor.setStandardizationType(Reactor.POST);

3. Set Reactor parameters (optional):

reactor.setReverse(true); // reverse reaction

reactor.setProductIndexes(new int[] {1}); // only first product

Reactor API – part II.

4. Set the reaction:• reactor.setReaction(rmol); // rules in rmol or no rules

• reactor.setReaction(rmol, reactivity, selectivity); // rules

• reactor.setReactionString(rstr); // SMARTS (with rules)

5. Set the reactants:

reactor.setReactants(new Molecule[] {r1, r2});

6. Process the reaction:

Molecule[] products = null;

while ((products = reactor.react()) != null) {

// do something with the products

}

Reactor API – examples I.

Reactor API – examples II.

Reactivity rule:!(match(ratom(3), '[#7:1]', 1) && pKa(ratom(3), 'basic') <

0.0)

&& !match(ratom(3), '[N,O,S:1][C,P,S]=[N,O,S]', 1)

Reactor API – examples III.

Reactants: Product:

Command line tool react:

Reactor API – examples IV.

Reactor API – examples V.

Reactants: The reactivity rule excludesthe N atom with negativebasic pKa.

reactive N atom

Reactor API – examples VI.

The result reaction:

Command line tool react:

Reactor API – examples VII.

Processing reactants in combinatorial mode:

Reactor API – examples VIII.

Time result for a 10x10 example, producing 120 products:

Command line tool react:

Observe the –m comb option for setting combinatorial mode.

Reactor speed test

Time result for a 326x2955 example, producing over

1 million products in about 3 hours with the command line tool react:

System configuration:CPU: intel P4 1.6 GHzRAM: 512 MBOS: RedHat 9, kernel 2.4.20-8Java: 1.4.2

Reactor JSP application

web: http://www.jchem.com/examples/reactor/jsp/index.jsp

• Graphical user interface

• Reaction / reactant setting: select from built-in reaction library load from file / SMARTS string draw in msketch set / modify reaction rules use example reactants from reaction

• Reaction processing: sequential or combinatorial mode product only or reaction form save results

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info@chemaxon.com

www.chemaxon.com

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