Reactor and Metabolizer
in vitro, in vivo and in situ in silico
•Solutions for Cheminformatics

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.

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 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

Example Results

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), \"[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)

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), \"aromaticsystem\") < -0.2

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), \"aromaticsystem\") < -0.2
TOLERANCE: 0.02

Results with Rules

Reactor Demo

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

Metabolizer

Metabolizer
• Enumerates the metabolites of a given
substrate
• Estimates metabolic stability
• Predicts major metabolites
• Human xenobiotic phase I. CYP450
biotransformation library is under
development

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

The Metabolism Model

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

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.

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

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).

• Thank you for your attention!
• For more information please visit
www.chemaxon.com