•Solutions for Cheminformatics

Reactor and Metabolizer

in vitro, in vivo and in situ in silico

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 atomL[O, S] oxygen or sulfur atomL[Cl, Br, I] chlorine, bromine or iodine atom

Example Results

Exclude “Sensitive” ReactantsExclude 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/DeactivationThe 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

RegiospecifityThe 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") < -0.2TOLERANCE: 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

( )maxv

vmaxS −=1

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

0

21 3

2 3 5

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

TransmissivitySpeed ratio of the consumption and production reactions of a metabolite.

ProductionThe relative “material flow” to a metabolite.

AccumulationRelative 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).

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