Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals
description
Transcript of Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals
![Page 1: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/1.jpg)
Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals
1
2nd McKim Workshop on Reducing Data Redundancy in Cancer AssessmentBaltimore, 8-10 May 2012
Ovanes Mekenyan, Milen Todorov, Ksenia Gerova
Laboratory of Mathematical Chemistry, Bulgaria
![Page 2: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/2.jpg)
2
Outlook
• Goal• Methods• Data• Predicting:
• AMES mutagenicity without metabolic activation• AMES metabolic activation chemicals negative as parents• Illustrating metabolic activation • False positives after metabolic activation• False negatives after metabolic activation
• Conclusions
![Page 3: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/3.jpg)
3
Outlook
• Goal• Methods• Data• Predicting:
• AMES mutagenicity without metabolic activation• AMES metabolic activation chemicals negative as parents• Illustrating metabolic activation • False positives after metabolic activation• False negatives after metabolic activation
• Conclusions
![Page 4: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/4.jpg)
4
• Predicting indirect DNA damage in the General Workflow Diagram for screening large chemicals inventories for carcinogenicity
Goal
![Page 5: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/5.jpg)
5
General Flow Diagram for Screening Large Inventories for carcinogenicity
Inventory
Direct DNA Reactive
Chemicals
DNA reactiveMetabolites
Ames Positive with S9
Ames Positive w/o S9
Classify asGenotoxic Bacterial Mutagen
High Carcinogenicity
Potential?
Generate metabolites
YY
Receptor-Based Screening
Low Carcinogenit
Potential
Y
N
Y Y
Protein Reactive
Chemicals
High Priority for Tumor
Promotion Assays
No-ThresholdRisk Assessment
CTA Assays for Nongenotoxic/
EpigeneticChemicals
Intermediate Priority for
Tumor Promotion
AssaysThreshold EffectRisk Assessment
![Page 6: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/6.jpg)
6
General Flow Diagram for Screening Large Inventories for carcinogenicity
Inventory
Direct DNA reactive
Indirect DNA reactive
Ames Positive with S9
Ames Positive w/o S9
Bacterial Mutagen
Chrom Ab ?MicroNucl ?
Protein OASIS
Generate metabolites
N
Y
Y
Receptor-Based Epigenetic
Screen
Low Carcinogenit
Potential
Y
Chrom Ab ?MicroNucl ?
Refine TIMES/Structural alerts
N
YY
N
Oxidative stress?
In vivo Mammal Tests
Protein Reactive
Return for further screening
![Page 7: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/7.jpg)
7
Outlook
• Goal• Methods• Data• Predicting:
• AMES mutagenicity without metabolic activation• AMES metabolic activation chemicals negative as parents• Illustrating metabolic activation • False positives after metabolic activation• False negatives after metabolic activation
• Conclusions
![Page 8: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/8.jpg)
DNA binding profile by OASIS
DNA binding profile by OECD
8
Methods:
• QSAR Toolbox profiles for DNA binding
![Page 9: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/9.jpg)
Illustration of the DNA binding profile of the QSAR Toolbox
9
![Page 10: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/10.jpg)
![Page 11: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/11.jpg)
Known DNA (covalent) binding mechanisms
![Page 12: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/12.jpg)
Known DNA (covalent) binding mechanisms
![Page 13: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/13.jpg)
Structural boundaries of the category
![Page 14: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/14.jpg)
Structural boundaries of the category
![Page 15: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/15.jpg)
DNA binding profile by OASIS
DNA binding profile by OECD
25
Methods:
• QSAR Toolbox profiles for DNA binding
• TIMES Metabolic simulator for rat liver S9
![Page 16: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/16.jpg)
OASIS Metabolic Simulator
• Prioritized list of non-enzymatic (abiotic) and enzymatic molecular transformations;
• Molecular transformations are characterized by:
Source and product fragments;Inhibiting “masks” preventing the
application of metabolic reactions if necessary;
• Substructure-matching software engine applies the simulated biochemical
• Reproduces the documented metabolic pathways and toxicity endpoint resulting from metabolic activation of chemicals
26
![Page 17: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/17.jpg)
Illustration the OASIS Metabolic Simulators
(extract from the Rat in vivo metabolism simulator)
27
![Page 18: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/18.jpg)
28
Substrate Principle transformations MetabolitesSimulator of metabolismSimulator of metabolism
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
Aliphatic C-oxidation
C CH2OH C C
O
H
Epoxide Hydration
C C
O
C C OHHO
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
![Page 19: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/19.jpg)
29
Substrate Principle transformations MetabolitesSimulator of metabolismSimulator of metabolism
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
Aliphatic C-oxidation
C CH2OH C C
O
H
Epoxide Hydration
C C
O
C C OHHO
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.90
P= 0.93
P= 0.94
P= 0.95
P= 0.96
P= 0.97
![Page 20: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/20.jpg)
30
Substrate Principle transformations Metabolites
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
Aliphatic C-oxidation
C CH2OH C C
O
H
Epoxide Hydration
C C
O
C C OHHO
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
CH2C CH3
- Isopropenylbenzene
![Page 21: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/21.jpg)
31
Match? - No! C CH2OH C CO
H
Substrate Principle transformations Metabolites
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
C C
O
C C OHHO
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
Aliphatic C-oxidationCH2C CH3
P= 0.97
Epoxide Hydration
- Isopropenylbenzene
![Page 22: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/22.jpg)
32
C CH2OH C C
O
H
Substrate Principle transformations Metabolites
P= 0.97
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
C C
O
C C OHHO
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.94
P= 0.93
P= 0.90
P= 0.95
CH2C CH3
P= 0.96
Aliphatic C-oxidation
Epoxide Hydration
- Isopropenylbenzene
![Page 23: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/23.jpg)
33
Match? - No! C C
O
HO C C OH
Substrate Principle transformations Metabolites
C CH2OH C C
O
H
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
Aliphatic C-oxidation
C C
O
HC C
O
OH
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.94
P= 0.95
CH2C CH3
P= 0.93
P= 0.90
O-Glucuronidation
P= 0.96
Aliphatic C-oxidation
Epoxide Hydration
P= 0.97
- Isopropenylbenzene
![Page 24: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/24.jpg)
34
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
RESULTMatch? - Yes!C
H2CCH3
OC
H2C CH3
P= 0.95
C CH2OH C C
O
H
Aliphatic C-oxidation
C C
O
C C OHHOP= 0.96
Epoxide Hydration
Aliphatic C-oxidation
C CH3 C CH2OH
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.94
P= 0.93
P= 0.90
P= 0.97
Generated map
1.1
Epoxidation
- Isopropenylbenzene
![Page 25: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/25.jpg)
35
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
RESULTMatch? - Yes!
CH2C CH3
C CH3 C CH2OH
CC CH2OHH2
P= 0.94
C CH2OH C C
O
H
Aliphatic C-oxidation
P= 0.96
Epoxide Hydration
C C
O
C C OHHO
Epoxidation
C C C C
O
P= 0.95
Aliphatic C-oxidation
C C
O
HC C
O
OH
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.93
P= 0.90
O-Glucuronidation
P= 0.97
- Isopropenylbenzene
1.1
C-oxidation
1.2
Generated map
Epoxidation
![Page 26: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/26.jpg)
36
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
C CH2OH C C
O
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
C C
O
C C OHHO
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?
CH2C CH3
C CH3 C CH2OH
- No!
P= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
Generated map
Epoxidation C-oxidation
- Isopropenylbenzene
1.1 1.2
![Page 27: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/27.jpg)
37
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
C CH2OH C C
O
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
C C
O
C C OHHO
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?
CH2C CH3
- No!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
Generated map
Epoxidation C-oxidation
- Isopropenylbenzene
1.1 1.2
![Page 28: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/28.jpg)
38
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
C CH2OH C C
O
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
C C
O
C C OHHO
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match? - No!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
Generated map
Epoxidation C-oxidation
1.1 1.2
CH2C
OCH3
- Metabolite 1.1
![Page 29: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/29.jpg)
39
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
C CH2OH C C
O
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?- Yes!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
CH2C
OCH3
C C
O
HO C C OH RESULT
C OH
OH
CH2
1.1 1.2
2.1
Hydration
C-oxidationEpoxidation
Generated map- Metabolite 1.1
![Page 30: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/30.jpg)
40
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?- Yes!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
1.1 1.2
RESULTC OH
OH
CH2
- Metabolite 2.1
C C
O
C C OHHO
C CH2OH C CO
H
C OH
O
CH2
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
![Page 31: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/31.jpg)
41
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?- Yes!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
1.1 1.2
RESULT
C C
O
C C OHHO
C CH2OH C CO
H 1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
- Metabolite 1.2.
CC CH2OHH2 O
C
HCCH2
C-oxidation2.2
![Page 32: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/32.jpg)
42
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?- No!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
1.1 1.2
C C
O
C C OHHO
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
- Metabolite 2.2.
OC
HCCH2
C-oxidation2.2
C CH2OH C C
O
H
![Page 33: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/33.jpg)
43
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?- No!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
1.1 1.2
C C
O
C C OHHO
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
OC
HCCH2
C-oxidation2.2
C CH2OH C C
O
H
- Metabolite 2.2.
![Page 34: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/34.jpg)
44
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
Epoxidation
Match?- Yes!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.96
P= 0.97
1.1 1.2
C C
O
C C OHHO
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
OC
HCCH2
C-oxidation2.2
C CH2OH C C
O
H
C C
O
C C
(Conjugated aldehyde group prevents epoxidation)
- Metabolite 2.2.
![Page 35: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/35.jpg)
45
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
Epoxidation
Match?- No! C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.96
P= 0.97
1.1 1.2
C C
O
C C OHHO
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
OC
HCCH2
C-oxidation2.2
C CH2OH C C
O
H
C C
O
C CP= 0.95
- Metabolite 2.2.
![Page 36: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/36.jpg)
46
Aliphatic C-oxidation
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
Epoxidation
Match?- Yes!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.96
P= 0.97
1.1 1.2
C C
O
C C OHHO
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
OC
HCCH2
C-oxidation2.2
C CH2OH C C
O
H
C C
O
C CP= 0.95
C C
O
H
C C
O
OH
RESULT
OC
CCH2
OH
3.2
C-oxidation
- Metabolite 2.2.
![Page 37: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/37.jpg)
Metabolic SimulatorsBridging the “Parent Gap”
Virtual metabolism uses a heuristic substructure search engine applied to a hierarchy of possible molecular transformations
Library ofBiotransformations& Abiotic Reactions
Documented Partial Maps
Algorithm for optimizingTransformationProbabilities
(Rate constants)
MetabolicMaps and ReactivityProfiles
Metabolic Simulators
ParentChemicals
![Page 38: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/38.jpg)
Simulated Metabolic Activation of 2-AcetylaminofluoreneSimulated Metabolic Activation of 2-Acetylaminofluorene(AMES mutagenicity in Rat liverS9)(AMES mutagenicity in Rat liverS9)
NH
O
NH
O
OH
NH
O
O
NH2
O
HO
O
NHOH
O
N+HO
NH
OHO
NH
O
O
NH
O
O
NH
OHO
NH
OHO
OHNH
OHO
OH
NH
OHO
O
NH
OHO
O
N+H
HO
ON+H
OH
O
. . . . . .
NHX
OO
X = H, OH,
O
Activated metabolites
Documented
![Page 39: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.fdocuments.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/39.jpg)
The OASIS Simulators of Mammalian Metabolism
•Liver S9 metabolism
•Different level of biological organisms (US EPA)Rat liver subcellular (microsomal)Rat liver cellular (in vitro)Organism (in vivo)
•In vivo metabolism – rat liver (in vivo MNT)In vivo detoxification logicIn vivo bioactivation
•Skin metabolism