zeneth 8: a faster, more intuitive, degradation predictive system 8...formula of yellow line = max...
TRANSCRIPT
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Zeneth 8: A faster, more intuitive,
degradation predictive system
Dr Martin Ott (Head of Chemistry)
Dr Ash Ali (Senior Scientist)
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Contents
• Zeneth 8 overview
Knowledge manager
Predictor
• Transformations and patterns
• Degradant scoring
• Excipient functionality
• New scientific developments
Stereochemistry
pKa calculator
• Demonstration
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Expert knowledge-based system for the prediction of forced degradation
Zeneth 8
Query
compound
Environmental
conditions“Predictor”
• H2O (hydrolysis)
• O2, H2O2, AIBN (oxidation)
• Light (photochemistry)
• pH
• Temperature
Potential degradants
Other
constraints
• Transformations [507]
• Excipients [189]
• References [546]
Knowledge
base
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Knowledge manager
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Knowledge manager
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Knowledge manager
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Knowledge manager
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Transformation patterns
z457:
Photodecarboxylation
of aryloxyacetic acid
Atom 13: requiredBondType(AROMATIC)
Atoms 16, 17: (heteroCount == 0 and allowedBondType(SINGLE))
or requiredBondType(AROMATIC)
Explora pattern language
Pattern 1
Prediction
breakBond(10, 15);
hideStructure(15);
breakBond(8, 9);
setBondType(9, 10, DOUBLE);
hideStructure(9);
setCharge(8, -1);
captureIntermediate("");
setIntermediateTypeMechanistic();
setIntermediateAsPresumed();
unsetCharge(8);
setScore(0.7); LTL
2 Script
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Zeneth prediction
QQuery Compound
Environmental
Conditions
• Water
• pH 3
Structure perception:
valences, rings, aromaticity
Match pattern
and conditions
No
Prediction
Generate
potential degradants
“Predictor”Knowledge
Base
pH profile
“Hydrolysis of acetal”
• requires water
• catalysed by acid
Prediction score = 700
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Degradant likelihood/scoring
Many transformations have a pH profile:
pH
Pre
dic
ted
lik
elih
ood
Formula of yellow line = MAX (1 − pH / 10, 0.1); x 1000 score
800
700
600
pH 3.9 likely
pH 3 likely
pH 2 likely
pH 1.9 very likely
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Scoring and multiplied step likelihood
Child degradant can never have a higher score than the parent
300 (Unl)
Individual step likelihoods
Q
500 (Eq)
D1
D2
D3
700 (Lik)
2nd Gen.
1st Gen.
3rd Gen.
“Lowest step”pathway
likelihoods
Q
500D1
D3
500
300
D2
Q
D1
D2
D3
350 [0.50 x 0.70 = 0.35]
105 [0.35 x 0.30]
500
“Multiplied step”pathway
likelihoods
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Excipients
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Building the knowledge base
Knowledge base
• External requests (members)
- provide data for a reaction
- proprietary data via data sharing initiatives
• Group discussion with members
- discuss proposals for new reactions
- provide feedback on new & existing chemistry
• Internal requests, updates to existing knowledge
- general maintenance
- investigation of primary literature
- specialised degradation chemistry books
• Strategic decision (e.g. cover a new reaction type)
0
100
200
300
400
500
600
2008 2010 2012 2014 2016 2018 2020
New knowledge added & existing
knowledge continuously maintained
Oxidation [148]
Hydrolysis [118]
Condensation [109]
Elimination [60]
Isomerisation [28]
Photolysis [44]
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New developments
• Stereochemistry
• Three-component reactions
• Intramolecular reactions
• Chemical descriptors / calculators
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Stereochemistry
• Take into account stereodefinition
This transformation now operates only on carbon centres that have a defined stereocentre:
z045
No prediction
• Nucleophilic substitutions
SN2-type reactions exhibit inversion of configuration at a stereocentre:
z138
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Three-component reactions
• Three-component reactions can now be expressed and handled:
2 bidentate oxygen boric acid spiroborate anion
nucleophiles
z505
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Intramolecular reactions
More intramolecular transformations can now be written
• Cyclisations
• Cycloadditionsillustrated with the photochemical [2+2] addition of two alkenes
h
h
intermolecular
intramolecular
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Intramolecular reactions
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Chemical descriptors / calculators
• pKa
• Bond Dissociation Energy (BDE)
• Electrophilicity/Nucleophilicity
• Photochemical Reactivity
• Aromaticity
• Steric Hindrance
Reasoning Engine
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C1
C4
pKa Calculator implemented
z045: Epimerisation alpha to electron-withdrawing group
Epimerisation is more likely at C1 than C4
if (!isDefinedStereocentre(1)) { abort(); }if (isBridgehead(1)) { abort(); }
substitutionWithInversion(4, 1, 3);hideStructure(3);
real pH = getpH();real pKa = getpKa(1);real raw_score = (max(pH, 14 - pH) + 6 - pKa) / 10;if (raw_score < 0.1) { abort(); }
setScore(min(raw_score, 0.9));
Score depends on pKa as well as on pH
pH = 12
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Zeneth 8 demo
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Zeneth 8: A faster, more intuitive,
degradation predictive system
Dr Martin Ott (Head of Chemistry)
Dr Ash Ali (Senior Scientist)
Software demonstration slides
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Intro screen
• Projects area
Start
new project
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Query: PU-H71
Conditions: oxygen, light, pH 11, temperature 20
°C
Pathway length: 2 steps
Minimum score: 600
Reaction types: all options off (= “no dimerisations”)
Pathway likelihood calc.: multiplied step
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Project screen
• Empty to start with
• Click on “chalk” (edit icon) to enter query structure
Create new
query structure
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Structure editor
• Draw a query structure or import one from file (.cdx, .mol)Use this structure
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Project screen
• With query structure
• Click on “i” (info icon) to display details on query structure
Settings for processing
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Settings
• Conditions
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Settings
• Other:
Reaction types
Numerical settings
Pathway likelihood calculation
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Project screen
• With query structure
• Click on “arrow right” icon to start processing query
Start processing
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Project screen
• Processing completed
• Click on “View results” to view tree
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Results
• Tree
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Results
• Table
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Query: Adrenaline
(epinephrine)
Conditions: oxygen, light, pH 11, temperature 20
°C
Pathway length: 3 steps
Minimum score: 600
Reaction types: all options off (= “no dimerisations”)
Pathway likelihood calc.: multiplied step
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Project screen
• Processing completed
• Click on “View results” to view tree
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Results
• Tree
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Results
• Tree
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Results
• Tree
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Query: Boric acid
Conditions: oxygen, light, pH 11, temperature 20 °C
Pathway length: 2 steps
Minimum score: 600
Reaction types: all options off (= “no dimerisations”)
Pathway likelihood calc.: multiplied step
Excipient(s): Glycerol
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• Add an excipient
Project screen
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Project screen
• Query structure with added excipient
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Project screen
• Processing completed
• Click on “View results” to view tree
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Results
• Tree
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Results
• Tree with intermediates
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Results
• Table
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Query: Altrenogest
Conditions: oxygen, light, pH 11, temperature 20 °C
Pathway length: 2 steps
Minimum score: 600
Reaction types: all options off (= “no dimerisations”)
Pathway likelihood calc.: multiplied step
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Project screen
• Processing completed
• Click on “View results” to view tree
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Results
• Tree
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Results
• Table
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Epimerisation / pKa
Conditions: oxygen, light, pH 7 or 11, temperature 20
°C
Pathway length: 2 steps
Minimum score: 600
Reaction types: all options off (= “no dimerisations”)
Pathway likelihood calc.: multiplied step
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Results
• Tree
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Results
• Tree
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Stereochemistry / SN2
Conditions: oxygen, light, pH 11, temperature 20 °C
Pathway length: 2 steps
Minimum score: 600
Reaction types: all options off (= “no dimerisations”)
Pathway likelihood calc.: multiplied step
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Results
• Tree
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Timing experimentComparison with Zeneth 7
Vary between
“lowest step” and
“multiplied step”
Vary between
≥ 400 (≥ equivocal)
and ≥ 600 (≥ likely)
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Speed improvement
Zeneth 8 takes about 13%* of the time taken by Zeneth 7 for the same query
Zeneth 7 Zeneth 8
SettingsPathway
likelihood calc.Settings
Pathway
likelihood calc.
Likelihoo
d
threshold
Lowest
step
Multiplie
d
step
Score
threshold
Lowest
step
Multiplie
d step
≥
equivocal
516
degs
288
degs≥ 400
534
degs
110
degs
488 sec 455 sec 57 sec 34 sec
≥ likely116
degs7 degs ≥ 600
129
degs9 degs
208 sec 65 sec 27 sec 9 sec
*: in the absence of excipients in the query
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Summary
➢ Zeneth is an expert knowledge-based system for the prediction of forced
degradation
➢ Helps understand mechanistic pathways as well as aid degradant
identification and structure elucidation
➢ Zeneth generates predictions from its knowledge base which currently
contains 507 transformations
➢ Our members drive the development of the Zeneth program and directly
influence the scientific content
➢ Zeneth has recently undergone a complete re-design with the result of
much improved usability as well as improvements to the quality and speed
of predictions.
➢ Efforts are underway to develop additional property
calculators and expand/improve the knowledge base,
more fully exploiting the added functionality
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Thank you for you attention!