Transcript ChemAxon Presentation

In Silico Synthesis
György 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
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
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);
Encoding Synthetic Knowledge in Reactions
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)
aromatic carbon atom
L[O, S]
oxygen or sulfur atom
L[Cl, Br, I]
chlorine, bromine or iodine atom
Encoding Synthetic Knowledge in Reactions
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
mono-halobenzenes.
Encoding Synthetic Knowledge in Reactions
Friedel-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 Reactions
Friedel-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 Reactions
Friedel-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
ChemAxon Reaction Library
Reactants
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
REACTOR
Products
Reactor, key features
Effective
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millions of compounds in a combinatorial reaction
up to 500,000 compounds / hour (P4 1.8 GHz)
Compatible
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reactions: MRV, RXN, RDF, SMARTS/SMIRKS
compounds: MRV, MOL, SDF, SMILES
mapping: MDL, Daylight, automapper
Flexible
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memory, file and database operations (even via Oracle Cartridge)
sequential or combinatorial mode
compound or reaction output type
reverse direction
Smart
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chemo-, regio- and stereospecific
customizable
Available
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Java API, command line tool, JSP
built-in reaction library
documentation and examples
free for the Academic community
Real Combinatorial Synthesis
alkyne coupling
lacton aminolysis
esterification
Derek S. Tan, Michael A. Foley, Matthew D. Shair, Stuart L. Schreiber*, J. Am. Chem. Soc., 1998, 120, 8565-8566
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.
4.
2.
5
3.
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:
Command line tool react:
Product:
Reactor API – examples IV.
Reactor API – examples V.
Reactants:
The reactivity
rule excludes
the N atom
with negative
basic 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 GHz
RAM:
512 MB
OS:
RedHat 9, kernel 2.4.20-8
Java:
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
Thank you for your attention
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Budapest, 1037
Hungary
[email protected]
www.chemaxon.com