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Reactor and Metabolizer



in vitro, in vivo and in situ in silico



                                          •Solutions...
Reactor
Reactor is an engine for the conversion of starting
compounds to products according to a given reaction
scheme
Som...
A Classic Reaction Example
The Generic Reaction Scheme
The hydrogen of an aromatic carbon atom is substituted
with an acyl group of an acid halide du...
Example Results
Exclude “Sensitive” Reactants
Exclude acrylic halides and aromatic compounds containing
nucleophilic groups. For example, ...
Activation/Deactivation
The generic reaction is unselective, but additional rules improve the
prediction. Friedel-Crafts a...
Regiospecifity
The electrophilic substitution takes place on the aromatic carbon
atom with the lowest localization energy ...
Results with Rules
Reactor Demo
Future Plans
• Multiprocessor and multicomputer support
• Reactant ratio
• All isomers in a single reaction output
• Multi...
Metabolizer
Metabolizer
• Enumerates the metabolites of a given
  substrate
• Estimates metabolic stability
• Predicts major metabolit...
Metabolic Stability Prediction

                                                    max(v )
                    0

       ...
The Metabolism Model
Major Metabolite Prediction, Assumptions
• all metabolites are produced from a single original
  substrate
• the metabolic...
Key Indicators
Transmissivity
Speed ratio of the consumption and production reactions of a metabolite.



Production
The r...
Biotransformation Speed
The reaction speed estimation could be based on
• calculations from the given substrate
   – It is...
Plans for the release and after
• Biotransformation library
   – Test and review each reaction of the current library
   –...
• Thank you for your attention!
• For more information please visit
  www.chemaxon.com
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Reactor Metabolizer virtual reactions for discovery: US UGM 2008

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ChemAxon developed a unique virtual reaction technology that could be applied in various areas of molecule transformations. Reactor is a virtual combichem application providing synthetically feasible products using generic reactions. No reagent selection is required, and built in rules can provide chemo- regio- and stereospecificity during the library enumeration progress. A new application using the same reaction engine is introduced for the first time for the prediction of metabolic stability and xenobiotic metabolites. For latest developments see: http://www.chemaxon.com/product/reactor.html

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Reactor Metabolizer virtual reactions for discovery: US UGM 2008

  1. 1. Reactor and Metabolizer in vitro, in vivo and in situ in silico •Solutions for Cheminformatics
  2. 2. Reactor Reactor is an engine for the conversion of starting compounds to products according to a given reaction scheme Some applications are built on this engine, one is for combichem reaction processing.
  3. 3. A Classic Reaction Example
  4. 4. The Generic Reaction 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
  5. 5. Example Results
  6. 6. Exclude “Sensitive” Reactants Exclude acrylic halides and aromatic compounds containing nucleophilic groups. For example, phenols and indols can be processed, but benzylalcohols and anilines should not. REACTIVITY: match(reactant(1), quot;[Cl,Br,I]C(=[O,S])C=Cquot;) || match(reactant(0), quot;[H][O,S]C=[O,S]quot;) || match(reactant(0), quot;[P][H]quot;) || (max(pka(reactant(0), filter(reactant(0), quot;match('[O,S;H1]')quot;), quot;acidicquot;)) > 14.5) || (max(pka(reactant(0), filter(reactant(0), quot;match('[#7:1][H]', 1)quot;), quot;basicquot;)) > 0)
  7. 7. Activation/Deactivation The generic reaction is unselective, but additional rules improve the prediction. Friedel-Crafts acylation occurs only if the aromatic system is at least as activated as mono-halobenzenes. REACTIVITY: charge(ratom(1), quot;aromaticsystemquot;) < -0.2
  8. 8. Regiospecifity 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. REACTIVITY: charge(ratom(1), quot;aromaticsystemquot;) < -0.2 TOLERANCE: 0.02
  9. 9. Results with Rules
  10. 10. Reactor Demo
  11. 11. Future Plans • Multiprocessor and multicomputer support • Reactant ratio • All isomers in a single reaction output • Multistep reactions (intermedier calculations) • Reactant statistics (success rate for combichem) • User interface simplifications (sketching in the wizard) • Reaction library – improvement of existing reactions – new reactions • Manual reaction site assignment • Integration with Instant JChem
  12. 12. Metabolizer
  13. 13. Metabolizer • Enumerates the metabolites of a given substrate • Estimates metabolic stability • Predicts major metabolites • Human xenobiotic phase I. CYP450 biotransformation library is under development
  14. 14. Metabolic Stability Prediction max(v ) 0 2 3 5 S = 1− vmax 1 2 3 max(v) is the speed category of the fastest consumption reaction of the given substrate (1: very slow, 2: slow, 3: medium, 4: fast, 5: very fast) vmax is the fastest speed category (5) In the example above, the metabolic stability of the substrate: S = 1 – 5/5 = 0
  15. 15. The Metabolism Model
  16. 16. Major Metabolite Prediction, Assumptions • all metabolites are produced from a single original substrate • the metabolic pathway of a substrate is known or predicted • The speed of each metabolic transformation is known or predicted, and it is constant independently from the substrate or metabolite concentration • the amount of the original substance is unknown, but it is not consumed completely • various routes can lead to the same metabolite • no cycles • the effect of excretion can be included as a metabolic reaction
  17. 17. Key Indicators Transmissivity Speed ratio of the consumption and production reactions of a metabolite. Production The relative “material flow” to a metabolite. Accumulation Relative growth rate of a metabolite calculated from the transmissivity and production values. Metabolites with the highest accumulation rates are the major metabolites.
  18. 18. Biotransformation Speed The reaction speed estimation could be based on • calculations from the given substrate – It is applicable for very few reaction types only • the similarity analysis of the same reaction with other substrates – Measurements are available for few reaction types only and the published results are not consistent • estimated for each reaction type – Raw method that does not consider the substrate dependence, but it is trainable
  19. 19. Plans for the release and after • Biotransformation library – Test and review each reaction of the current library – Refine reaction speed values manually, perhaps computationally – Validate major metabolite prediction with published drug metabolism data • Finish the design of the graphical user interface • Provide a biotransformation library of reactive intermediates (useful for hepatotoxicity risk indication).
  20. 20. • Thank you for your attention! • For more information please visit www.chemaxon.com

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