Virtual ICH M7 Expert Review Workshop Dr. Sian Ives Sales Manager - - PowerPoint PPT Presentation

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Virtual ICH M7 Expert Review Workshop Dr. Sian Ives Sales Manager - - PowerPoint PPT Presentation

Nov 04, 2022 35 likes •1.08k views

Virtual ICH M7 Expert Review Workshop Dr. Sian Ives Sales Manager sian.ives@lhasalimited.org ICH M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Identification

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Virtual ICH M7 Expert Review Workshop

Sales Manager

sian.ives@lhasalimited.org

  • Dr. Sian Ives
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ICH M7

“Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk”

Identification Categorisation Qualification Control

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ICH M7 section 6

  • Hazard assessment involves an initial analysis of actual and

potential impurities by conducting database/literature searches

  • You may use the Ames (in vitro) assay to characterise risk/hazard
  • Or use in silico mutagenicity predictions in its place
  • If you submit in silico predictions, you will need:
  • Two predictions: one expert rule-based and one statistical-based
  • “The absence of structural alerts from both is sufficient to

conclude that the impurity is of no mutagenic concern”

  • Expert review
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In silico workflow under M7

Evaluate drug substance, impurities, degradants, intermediates Databases, in-house, literature Known mutagen Limit according to TTC or present purge argument for loss Treat as non- mutagenic Known non-mutagen

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What is Vitic?

  • Structure searchable toxicity database and chemical

database management system

  • Public toxicity data
  • You can add your own private, in-house data
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Vitic 2018.1 database

  • 20,580 substances
  • Key endpoint record count:
  • Overall call

10,930 substances 39,435 records

  • Genetox in-vitro summary 14,234 substances

17,216 records

  • Genetox in-vitro

13,657 substances 221,958 records

  • Genetox in-vivo

3,037 substances 12,671 records

  • Carcinogenicity

3,870 substances 16,464 records

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In silico workflow under M7

In silico predictions expert / statistical Evaluate drug substance, impurities, degradants, intermediates Databases, in-house, literature Known mutagen Limit according to TTC or present purge argument for loss Treat as non- mutagenic Known non-mutagen

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What is Derek Nexus?

  • Expert system for prediction of toxicology
  • Comprises of 132 Alerts for mutagenicity
  • Written by expert scientists from detailed expert analysis
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  • Alert screenshot
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Skin permeability Presence of toxicophore Molecular weight Species Metabolic activation

How does Derek Nexus predict?

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What is Sarah Nexus?

  • Statistical model for prediction of mutagenicity
  • Model uses a dataset of ~10K compounds
  • Uses a Self Organising Hypothesis Network (SOHN) methodology*

*Thierry Hanser, Chris Barber, Edward Rosser, Jonathan D Vessey, Samuel J Webb and Stéphane Werner: Self organising hypothesis networks: a new approach for representing and structuring SAR knowledge. Journal of Cheminformatics. 2014, 6:21.

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How does Sarah Nexus predict?

  • User enters query compound
  • Query compound is fragmented
  • Sarah uses the dataset to identify relevant hypotheses
  • A confidence value is calculated
  • Considering Ames Result and Similarity of supporting examples

… … Hypothesis 1: Hypothesis 2: POSITIVE 72% Confidence

Decreasing similarity

Supporting Examples: Supporting Examples:

Positive 65% confidence Positive 78% confidence

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ICH M7 classification tool

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In silico workflow under M7

Expert Review In silico predictions expert / statistical Evaluate drug substance, impurities, degradants, intermediates Databases, in-house, literature Known mutagen Both predict positive Both predict negative Ames test Limit according to TTC or present purge argument for loss Treat as non- mutagenic Known non-mutagen Disagree / fail to predict

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Virtual ICH M7 Expert Review Workshop

Senior Account Manager

accountmanagement@lhasalimited.org

  • Dr. Dave J. Yeo
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Introduction

  • Example compounds with conflicting expert rule-based

and statistical-based results

  • Derek and Sarah Results:
  • Will be presented
  • You will be asked to assess each example and vote

accordingly

  • Class 3 – Alerting structure. Control to TTC or test…
  • Class 5 – Treat as a non mutagen…
  • Unsure…
  • Lhasa will then present an expert call.*

*All expert calls made on the examples are solely the opinion of experts at Lhasa Limited and are made here for guidance purposes only

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Example 1

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Review high level predictions

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Expert Review M7 classification

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Review the expert prediction

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Expert Review M7 classification

  • Alert 346: Trichloromethyl aromatic compound
  • Any aromatic carbon linked to a trichloromethyl group.
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Review the statistical prediction

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Expert Review M7 classification

  • 50% Positive in Sarah Nexus
  • 5 most relevant nearest neighbours are all positive
  • Negative nearest neighbours are dissimilar (not trichloromethyl aromatic compounds).
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Expert review

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Expert Review M7 classification

  • Predicted positive
  • Fires alert 346: Trichloromethyl aromatic compound.
  • Predicted positive - 50% confidence
  • 5 most relevant nearest neighbours are all positive

and fire Derek alert 346.

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Please make your selection

  • 1. Class 3 – Alerting structure
  • 2. Class 5 – No alerts or alerting with sufficient data

to demonstrate lack of mutagenicity

  • 3. Unsure
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M7 Classification

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Expert Review M7 classification

Classification

  • Predicted positive by Derek Nexus (alert 346)
  • No reason to doubt alert
  • Predicted positive by Sarah Nexus
  • 100% confidence-exact match
  • 5 most relevant nearest neighbours are all positive

and fire Derek alert 346.

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M7 Classification

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Expert Review M7 classification

Class 3

Alerting structure

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Example 2

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Review high level predictions

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Expert Review M7 classification

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Review the expert system

  • No alerts fired
  • Potential aromatic amine present in the molecule.

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Expert Review M7 classification

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Review the statistical prediction

  • Two negative hypotheses.

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Expert Review M7 classification

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Review the statistical prediction

  • Parent amine present in similar Ames negative compounds.

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Expert Review M7 classification

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Expert Review

  • Inactive prediction
  • No misclassified or unclassified features.
  • Negative prediction
  • Compounds in the training set are similar and Ames

negative

  • Parent amine is Ames negative.

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Expert Review M7 classification

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Please make your selection

  • 1. Class 3 – Alerting structure
  • 2. Class 5 – No alerts or alerting with sufficient data

to demonstrate lack of mutagenicity

  • 3. Unsure
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M7 Classification – Example 2

  • Predicted inactive by Derek Nexus
  • No reason to overturn the prediction.
  • Predicted negative by Sarah Nexus
  • Closely related examples are Ames Negative.

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Expert Review M7 classification

Classification

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M7 Classification – Example 2

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Expert Review M7 classification

Class 5

No alerts or alerting with sufficient data to demonstrate lack of mutagenicity

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Example 3

Compound

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Review high level predictions

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Expert Review M7 classification

Compound Nexus - ICH M7 Summary result

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Review the expert prediction

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Expert Review M7 classification

  • Alert 318: Azide, hydrazoic acid or azide salt
  • Any atom linked to an azide group.
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Review the statistical prediction

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Expert Review M7 classification

An outside domain outcome was obtained as the current training set does not include any example covering the sulfonyl azide fragment.

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Review the statistical prediction

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Expert Review M7 classification

By replacing the outside domain sulfonyl azide fragment by an azidomethyl fragment, a positive prediction was reported matching the existing azide hypothesis.

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Additional information (from Vitic)

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Expert Review M7 classification

No Ames data available for N-(4-Azidosulfonylphenyl)acetamide (OOD)

  • r for N‐(4‐(Azidomethyl)phenyl)acetamide (predicted positive).

For the 1st nearest neighbour to N‐(4‐(Azidomethyl)phenyl)acetamide: Benzyl azide 622-79-7 (most relevant example), positive results observed in TA100+S9. Overall calls from various datasets for 622-79-7: Positive Ames data were reported for various benzyl azide derivatives.

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Expert review

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Expert Review M7 classification

  • Active prediction
  • Fires alert 318 for Azide, hydrazoic acid or azide salt
  • No data available to overturn the prediction.
  • Out of domain sulfonyl azide fragment
  • Sarah Nexus does have a positive hypothesis for azides.
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Please make your selection

  • 1. Class 3 – Alerting structure
  • 2. Class 5 – No alerts or alerting with sufficient data

to demonstrate lack of mutagenicity

  • 3. Unsure
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M7 Classification – Example 3

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Expert Review M7 classification

Classification

  • Positive prediction from Derek Nexus (alert 318)
  • No reason to doubt.
  • Out of domain in Sarah due to sulfonylazide fragment
  • Sarah Nexus has a positive hypothesis for azides.
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M7 Classification – Example 3

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Expert Review M7 classification

Class 3

Alerting structure

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Example 4

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Review high level predictions

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Expert Review M7 classification

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Review the expert prediction

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Expert Review M7 classification

  • Alert 027: Alkylating agent
  • No reason to doubt predicted activity.
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Review the statistical prediction

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Expert Review M7 classification

  • No hypothesis is identified
  • The relevant nearest neighbours are all positive and fire Derek alert 027
  • Negative nearest neighbours are dissimilar and are not alkylating agents.
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Expert review

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Expert Review M7 classification

  • Positive prediction
  • No reason to doubt.
  • Equivocal prediction
  • No hypothesis identified
  • Relevant nearest neighbours in the training set are positive
  • Nearest neighbours that are negative are dissimilar and are not

alkylating agents.

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Please make your selection

  • 1. Class 3 – Alerting structure
  • 2. Class 5 – No alerts or alerting with sufficient data

to demonstrate lack of mutagenicity

  • 3. Unsure
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M7 Classification – 5689-83-8

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Expert Review M7 classification

Classification

  • Derek Nexus
  • No reason to doubt Derek Nexus positive

prediction (alert 027)

  • Sarah Nexus
  • Equivocal prediction overruled as relevant

examples are positive

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M7 Classification – 5689-83-8

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Expert Review M7 classification

Class 3

Alerting structure

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Example 5

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Review high level predictions

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Expert Review M7 classification

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Review the expert prediction

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Expert Review M7 classification

  • Negative prediction
  • No misclassified or unclassified features.
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Review the statistical prediction

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Expert Review M7 classification No hypothesis is identified. Activity of nearest neighbours is associated with their ability to act as alkylating agents or the epoxide, neither are relevant to the query.

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Review the statistical prediction

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Expert Review M7 classification No hypothesis is identified. Parent alcohol and sulfonic acid are both negative examples in the training set.

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Expert review

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Expert Review M7 classification

  • Negative prediction
  • No misclassified or unclassified features.
  • Equivocal prediction
  • No hypothesis identified
  • Activity of nearest neighbours is associated with structural features

enabling them as alkylating agents

  • Parent alcohol and sulfonic acid are negative examples in the

training set.

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Please make your selection

  • 1. Class 3 – Alerting structure
  • 2. Class 5 – No alerts or alerting with sufficient data

to demonstrate lack of mutagenicity

  • 3. Unsure
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M7 Classification – Example 5

  • Derek Nexus
  • Inactive prediction with no misclassified or

unclassified features.

  • Sarah Nexus
  • Equivocal prediction overruled as positive examples

are not relevant and parent compounds are negative examples in the training set.

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Expert Review M7 classification

Compound

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M7 Classification – Example 5

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Expert Review M7 classification

Class 5

Class 5 - No alerts or alerting with sufficient data to demonstrate lack of mutagenicity

Compound

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Example 6

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Review high level predictions

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Expert Review M7 classification

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Review the expert prediction

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Expert Review M7 classification Alert 315: Acid halide Sulphonyl chloride functional group match sulphonyl halide toxicophore III However risk of false positives flagged in Ames tests in DMSO. [Amberg A et al., Organic Process Research and Development (2015), 19(11), 1495-1506] 5-strain Ames negative results for Benzene sulphonyl chloride (98-09-9) in acetonitrile.

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Additional information (from literature)

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Expert Review M7 classification

Amberg et al., Organic Process Research and Development (2015), 19(11), 1495-1506

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Additional information (From Vitic)

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Expert Review M7 classification

No Ames data available on 15945-07-0 2,4,5-Trichlorobenzenesulfonyl chloride 5-strain Ames negative results for Benzene sulphonyl chloride (98-09-9) in acetonitrile. [Amberg A et al., Organic Process Research and Development (2015), 19(11), 1495-1506] (false positives due to reactivity with DMSO discarded).

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Review the statistical prediction

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Expert Review M7 classification Compounds 1 and 7 confirmed absence of activity of benzene with chloro substituents.

Compounds from training set are dissimilar to the test compound. i.e., none of the examples contain a sulphonyl chloride group.

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Expert review

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Expert Review M7 classification

  • Predicted positive
  • Fires alert 315 for acid halide, however Ames

positive calls challenged as potential for false positives due to reactivity with DMSO

  • 5-strain Ames negative results for similar

compound benzene sulphonyl chloride (98-09-9) in acetonitrile.

  • Inactive prediction
  • Nearest neighbours from Sarah training dissimilar to

the test compound i.e. no sulfonyl chloride group.

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Please make your selection

  • 1. Class 3 – Alerting structure
  • 2. Class 5 – No alerts or alerting with sufficient data

to demonstrate lack of mutagenicity

  • 3. Unsure
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M7 Classification – Example 6

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Expert Review M7 classification

Classification

  • Derek positive prediction (alert 315)
  • Compound may react with DMSO to produce a reactive,

mutagenic intermediate

  • The alert fires to explain artefactual activity that may be seen
  • Similar compounds Ames negative in other solvents.
  • Sarah negative prediction
  • Nearest neighbours from Sarah training dissimilar to the test

compound i.e. no sulfonyl chloride group

  • Similar compound in the training set, benzene sulphonyl

chloride (98-09-9) is negative.

  • Overrule Derek prediction
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M7 Classification – Example 6

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Expert Review M7 classification

Class 5

No alerts or alerting with sufficient data to demonstrate lack of mutagenicity

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Example 7

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Review high level predictions

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Expert Review M7 classification

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Review the expert prediction

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Expert Review M7 classification

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Review the expert prediction

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Expert Review M7 classification

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Review the statistical prediction

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Expert Review M7 classification

Most training set examples have an aromatic group attached to the alkene (C3 position) which Derek Nexus has described as having decreased mutagenic activity.

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Review the statistical prediction

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Expert Review M7 classification

  • There is no protocol information.
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Expert review

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Expert Review M7 classification

  • Plausible prediction
  • Fires alert 664 for alpha,beta-unsaturated compounds
  • Mutagenicity related to electronegativity and steric hindrance

around the double bond

  • Aryl substituents at C3 are typically negative or reduced

mutagenicity.

  • Negative prediction
  • Negative compounds mostly have an aryl substituent at C3

position

  • Most similar compound, 30418-35-2 is negative however there is

no protocol information.

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Please make your selection

  • 1. Class 3 – Alerting structure
  • 2. Class 5 – No alerts or alerting with sufficient data

to demonstrate lack of mutagenicity

  • 3. Unsure
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M7 Classification – Example 7

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Expert Review M7 classification

  • Predicted positive
  • No data to support overturning the prediction.
  • Predicted inactive
  • Many of the supporting examples are not relevant.
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M7 Classification – Example 7

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Expert Review M7 classification

Class 3

Alerting structure

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Example 8

Compound

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Review high level predictions

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Expert Review M7 classification

Compound

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Review the expert prediction

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Expert Review M7 classification

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Review the expert prediction

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Expert Review M7 classification

  • Candidate for alert 351
  • Phenyl substitution of secondary amine excluded and electron withdrawing group

present on the aromatic ring deactivating

  • Primary amine group does not activate due to ortho aromatic amine substitution

which may cause steric hindrance.

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Review the statistical prediction

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Expert Review M7 classification

351

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Review the statistical prediction

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Expert Review M7 classification Good strain data for both negatives

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Expert review

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Expert Review M7 classification

  • Negative with no misclassified or unclassified features
  • Near miss of alert 351
  • Exclusion based on limitations in substitution allowed on second

amine group in ortho diamines

  • Exclusion based on available evidence rather than negative data.
  • Sarah Nexus identifies a positive hypothesis for aromatic amine

which is overruled by nearest neighbours

  • Two negative nearest neighbours are relevant and electronically

similar to both amines present in query structure

  • Data lacking for ortho-substituted aromatic amine and there is a

data gap for this sub-class.

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Please make your selection

  • 1. Class 3 – Alerting structure
  • 2. Class 5 – No alerts or alerting with sufficient data

to demonstrate lack of mutagenicity

  • 3. Unsure
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M7 Classification – Example 8

  • Derek inactive prediction
  • Exclusion from alert 351 based on steric hindrance

around aromatic amine

  • Query compound may adopt a conformation with less

steric hindrance and potential to intercalate.

  • Sarah negative prediction
  • Two most similar relevant examples negative
  • No data for this type of ortho substitution relating to

steric influence.

  • While there is limited data available relating to this type of
  • rtho substitution of an aromatic amine, the same

substitution in the para position gave negative results. No need to overturn Derek Nexus and Sarah Nexus.

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Expert Review M7 classification

Compound

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M7 Classification – Example 8

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Expert Review M7 classification

Class 5

No alerts or alerting with sufficient data to demonstrate lack of mutagenicity Compound

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Example 9

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Review high level predictions

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Expert Review M7 classification

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Review the expert prediction

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Expert Review M7 classification

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Review the statistical prediction

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Expert Review M7 classification

  • Equivocal prediction
  • Training set examples are not relevant to query
  • Check additional information…
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Review the statistical prediction

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Expert Review M7 classification

  • Close match with training set compound
  • Ames positive with results in two strains
  • No reason to doubt the positive.
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Expert review

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Expert Review M7 classification

  • Inactive prediction, however the compound contains misclassified

features.

  • Compound is in Lhasa reference Ames test dataset as a known

false negative.

  • Equivocal prediction
  • Additional information shows a closely related training set example
  • This example is Ames positive and no reason to doubt data.
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Please make your selection

  • 1. Class 3 – Alerting structure
  • 2. Class 5 – No alerts or alerting with sufficient data

to demonstrate lack of mutagenicity

  • 3. Unsure
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M7 Classification – Example 9

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Expert Review M7 classification

Class 3

Alerting structure

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Thank You