Predicting Estrogen Receptor Binding within Categories Rick Kolanczyk Environmental Protection...
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Transcript of Predicting Estrogen Receptor Binding within Categories Rick Kolanczyk Environmental Protection...
Predicting Estrogen Receptor Binding within Categories
Rick KolanczykEnvironmental Protection Agency
Office of Research and Development
National Health and Environmental Effects Research Laboratory
Mid-Continent Ecology Division
Duluth, MN
Estrogen Receptor Toxicity Pathway
• Need is derived from Food Quality Protection Act – “estrogens”
• Chemical binding to ER is known to cause adverse effects– Toxicity Pathway
• Diverse chemicals bind to ER
• Drug bioassays for ER binding are not relevant – drug-design assays optimized for high affinity binders– environmental hazard may come from low affinity binding
Development and use of a QSAR requires clear Problem Definition
• The purpose of the QSAR application must be well-defined (e.g., priority setting for testing, and chemical-specific risk assessment are two very different purposes)
• The chemicals of regulatory concern must be defined to develop a database of tested chemicals (training set) for QSAR development
EPA Office of Pesticide Programs:Food Use Inerts & Antimicrobials
– Get ‘lists’– Characterize structures– Assess coverage of existing data (training sets, TrSets)– Select chemicals for testing to strategically expand structure space
to maximize information gained from every structure tested
Defining the Problem: EPA Office of Pesticide Programs
Food Use Inerts List - Structures
List from OPP/RD included:
893 entries = 393 discrete chemicals + 500 non-discrete substances(44% discrete : 56% non-discrete)
393 discrete chemicals include:366 organics (93%)24 inorganics (6%)3 organometallics (1%)
500 non-discrete substances include:147 polymers of mixed chain length170 mixtures 183 undefined substances
Defining the Problem: EPA Office of Pesticide Programs
Antimicrobials/Sanitizers - Structures
Lists from OPP/AD included:
299 = 211 discrete chemicals + 88 non-discrete substances(71% discrete : 29% non-discrete)
211 discrete chemicals include:153 organics (72%) 52 inorganics (25%) 6 organometallics-acyclic (3%)
88 non-discrete substances include:25 polymers of mixed chain length35 mixtures 28 undefined substances
In-lab Testing = Training Set The Issue:Assay protocols optimized to increase confidence in quantifying activity of
low potency compoundsCompare EPA Office of Pesticide Programs chemical structures to existing
ER data
The assays:
1) ER binding –
• standard competitive binding assay optimized for low affinity binders
• Rainbow trout liver cytosol (rtER)
2) Gene Activation
• trout liver slice - vitellogenin mRNA
• Endogenous metabolism
Data Example – Pos. Binding; Pos. Gene Activation
rtER Gene ExpressionrtER Binding
CTRL0.00001
0.0001
0.001
0.01
0.1
1
10 P E2 control
PNMP
PNEP
PNPrP
PNBP
-10 -9 -8 -7 -6 -5 -4 -3 -2
Log Concentration (M)
Vtg
mR
NA
(F
ract
ion
of
max
imu
m E
2ef
fica
cy)
CTRL
0
10
20
30
40
50
60
70
80
90
100
110
120
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1
E2
P
PNEP
PNMP
PNBP
PNPrPPIPrP
Log Concentration (M)
[3H
]-E
2 B
ind
ing
(%)
Building a Decision Tree with Categories
Chemical Inventory
Contains CycleYes
Non binder(RBA<0.00001)
No
ChemicalInventory
Contains CycleYes
Yes
Belongs to known Inactive
class
Non binder(RBA<0.00001)
Alkylbenzsulfonic Acids• Sulfonic Acid Dyes• p-Alkyl Fluorobenzenes• Bis–anilines• Alkoxy Anilines• Imidazolidines• Isothiazolines• Alkyl Benzthiols• Pyrrolidiones
• Oxazoles• Benzamide• Furans• Sorbitans• Triazines
No
Alkylbenzsulfonic acids
-0.62 msrd
CH3 S
OH
O
O
3.56 calc.0.92 calc.
S
O
O
OH
S
O
O
OH
CH3
4.45 calc. 6.15 calc.
CH3
NH2
CH3CH3
NH2
CH3
CH3N
CH3
N
CH3
CH3
3.57 calc.
CH3
NH2
CH3
NH2
Bis-Anilines
O
CH3
O
OHOH
OH O
OH
O
O
CH3
O
OH
OH
3.15 calc. 5.89 calc.
Sorbitans Sulfonic acids dyes
0.61 calc. 2.45 msrd
O
S
N
CH3
O
NH
S
Isothiazolines
AYE -1.00 calc. RAC 0.08 calc.SYE -0.44 calc.
O-
SO
ON
N
NH
N
S
O-
OO
OH
O-
O
O-
SO
O
N
N
OH
SO
-
O
O
OH
N
N
O
CH3
S
O
O
OH
CH3
SO
O
OH
FUI AMI FUI
--0.86 calc. 0.39 calc.
O
CH3CH3
NOH
O
NH
O
CH3
CH3N
Br
O
N
Cl
Imidazolidines
-1.00 calc. -0.44 calc. 1.89 msrd
O-
SO
ON
N
NH
N
S
O-
OO
OH
O-
O
O-
SO
O
N
N
OH
SO
-
O
O
Cl
Cl
NH
O
NH
Cl
O Cl
SO
O
O-
ChemicalInventory
Contains CycleYes Contains 2 OH,
or OH and =0, at Spec. Dist
Yes
NoBelongs to known Inactive
class
Non binder(RBA<0.00001)
• Alkylbenzsulfonic Acids• Sulfonic Acid Dyes• p-Alkyl Fluorobenzenes• Bis–anilines• Alkoxy Anilines• Imidazolidines• Isothiazolines• Alkyl Benzthiols• Pyrrolidiones
• Oxazoles• Benzamide• Furans• Sorbitans• Triazines
No
R 394
E 353 H 524
BBAA
Schematic representation ofSchematic representation of ER binding pocket (LBD), with ER binding pocket (LBD), with 3 sites of interaction shown 3 sites of interaction shown (A, B, C), and ER protein a.a. (A, B, C), and ER protein a.a. involved in the interactions involved in the interactions which chemical ligands.which chemical ligands. CC
T 347
CC
J. Katzenellenbogen
R 394
E 353 H 524
CC
T 347
HOOH
CH3 H
H H
H
AA BB
A_B Interaction A_B Interaction
Distance = 10.8 for 17-Estradiol
ChemicalInventory
Contains CycleYes Contains 2 OH,
or OH and =0, at Spec. Dist
Possible High Affinity,“A-B”; “A-C”; or
“A-B-C” type binder
Contains some attenuating feature
steric?; other?
High Binding Affinity “A-B”;“A-C” or “A-B-C” type
No
Non binder Ex: ProgesteroneCorticossterone(RBA<0.00001)
Low Affinity Binder“A-B”,“A-C” or “A-B-C” type
Assess strength of attenuation steric?;
other?
Some
Complete
VYes
Yes
No
NoBelongs to known Inactive
class
Non binder(RBA<0.00001)
• Alkylbenzsulfonic Acids• Sulfonic Acid Dyes• p-Alkyl Fluorobenzenes• Bis–anilines• Alkoxy Anilines• Imidazolidines• Isothiazolines• Alkyl Benzthiols• Pyrrolidiones
Yes
• Oxazoles• Benzamide• Furans• Sorbitans• Triazines
No
No
ChemicalInventory
Contains CycleYes Contains 2 OH,
or OH and =0, at Spec. Dist
Possible High Affinity,“A-B”; “A-C”; or
“A-B-C” type binder
Contains some attenuating feature
steric?; other?
High Binding Affinity “A-B”;“A-C” or “A-B-C” type
No
Non binder Ex: ProgesteroneCorticossterone(RBA<0.00001)
Log Kow <1.3
Low Affinity Binder“A-B”,“A-C” or “A-B-C” type
Assess strength of attenuation steric?;
other?
Some
Complete
Contains at least
one possible
H-bonding site
V
Possible Low AffinityBinder
YesNo
Yes
No
NoBelongs to known Inactive
class
Non binder(RBA<0.00001)
• Alkylbenzsulfonic Acids• Sulfonic Acid Dyes• p-Alkyl Fluorobenzenes• Bis–anilines• Alkoxy Anilines• Imidazolidines• Isothiazolines• Alkyl Benzthiols• Pyrrolidiones
Yes
• Oxazoles• Benzamide• Furans• Sorbitans• Triazines
Yes
No
Yes
0.000001
0.00001
0.0001
0.001
0.01
0.1
0 1 2 3 4 5 6 7 8
LogKow
Lo
gR
BA
Additional 46 chemicals tested as non-binders with
LogKOW below 1.3
ChemicalInventory
Contains CycleYes Contains 2 OH,
or OH and =0, at Spec. Dist
Possible High Affinity,“A-B”; “A-C”; or
“A-B-C” type binder
Contains some attenuating feature
steric?; other?
High Binding Affinity “A-B”;“A-C” or “A-B-C” type
No
Non binder Ex: ProgesteroneCorticossterone(RBA<0.00001)
Log Kow <1.3
Low Affinity Binder“A-B”,“A-C” or “A-B-C” type
Assess strength of attenuation steric?;
other?
Some
Complete
Contains at least
one possible
H-bonding site
Type “A”Contains Phenol
Fragment
V
Possible Low AffinityBinder
No
YesNo
II
Yes
No
NoBelongs to known Inactive
class
Non binder(RBA<0.00001)
• Alkylbenzsulfonic Acids• Sulfonic Acid Dyes• p-Alkyl Fluorobenzenes• Bis–anilines• Alkoxy Anilines• Imidazolidines• Isothiazolines• Alkyl Benzthiols• Pyrrolidiones
Yes
• Oxazoles• Benzamide• Furans• Sorbitans• Triazines
Yes
No
Yes
R 394
E 353 H 524
CC
T 347
HOAA BB
““A_site only” Interaction A_site only” Interaction
CH3
ChemicalInventory
Contains CycleYes Contains 2 OH,
or OH and =0, at Spec. Dist
Possible High Affinity,“A-B”; “A-C”; or
“A-B-C” type binder
Contains some attenuating feature
steric?; other?
High Binding Affinity “A-B”;“A-C” or “A-B-C” type
No
Non binder Ex: ProgesteroneCorticossterone(RBA<0.00001)
Log Kow <1.3
Low Affinity Binder“A-B”,“A-C” or “A-B-C” type
Assess strength of attenuation steric?;
other?
Some
Complete
Contains at least
one possible
H-bonding site
Type “A”Contains Phenol
Fragment
V
Possible Low AffinityBinder
• Alkyl Phenols • Alkoxy Phenols• Parabens• Salicylates
Belongs to known Active
class
Potency Rules / Equations
No
YesNo
II
Needs testing
Yes
No
No
Yes
Belongs to known Inactive
class
• Fully-hindered Alkyl Phenols
Belong to untested classwith possible
Type A low affinity
Yes
Non binder(RBA<0.00001)
• Mixed Phenols
No
Yes
No
Belongs to known Inactive
class
Non binder(RBA<0.00001)
• Alkylbenzsulfonic Acids• Sulfonic Acid Dyes• p-Alkyl Fluorobenzenes• Bis–anilines• Alkoxy Anilines• Imidazolidines• Isothiazolines• Alkyl Benzthiols• Pyrrolidiones
Yes
• Oxazoles• Benzamide• Furans• Sorbitans• Triazines
Yes
No
Yes
3.20 msrd
OH
CH3
5.16 calc.
OH
CH3
CH3
CH3
CH3
CH3
Alkylphenols
3.57 msrd3.40 calc. 1.96 msrd
O
OH
O CH3
O
OH
O
CH3
CH3
O
OH
O
CH3
OH
O
O
CH3
5.43 calc.
Parabens
2.55 msrd 4.63 msrd 5.06 calc.
O
OH
O CH3
O
OH
O
CH3
O
O
CH3
OH
Salicylates
3.31 msrd
OH
CH3
CH3
CH3
4.06 msrd
OH
CH3
ChemicalInventory
Contains CycleYes Contains 2 OH,
or OH and =0, at Spec. Dist
Possible High Affinity,“A-B”; “A-C”; or
“A-B-C” type binder
Contains some attenuating feature
steric?; other?
High Binding Affinity “A-B”;“A-C” or “A-B-C” type
No
Non binder Ex: ProgesteroneCorticossterone(RBA<0.00001)
Log Kow <1.3
Low Affinity Binder“A-B”,“A-C” or “A-B-C” type
Assess strength of attenuation steric?;
other?
Some
Complete
Contains at least
one possible
H-bonding site
Type “A”Contains Phenol
Fragment
V
Possible Low AffinityBinder
Type “B”Contains identif. Type B
Fragment• Alkyl Phenols • Alkoxy Phenols• Parabens• Salicylates
Belongs to known Active
class
Potency Rules / Equations
No
YesNo
No
II
Needs testing
Yes
No
No
Yes
IIIBelongs to
known Inactive class
• Fully-hindered Alkyl Phenols
Belong to untested classwith possible
Type A low affinity
No
Yes
Non binder(RBA<0.00001)
• Mixed Phenols
No
YesIII
No
Belongs to known Inactive
class
Non binder(RBA<0.00001)
• Alkylbenzsulfonic Acids• Sulfonic Acid Dyes• p-Alkyl Fluorobenzenes• Bis–anilines• Alkoxy Anilines• Imidazolidines• Isothiazolines• Alkyl Benzthiols• Pyrrolidiones
Yes
• Oxazoles• Benzamide• Furans• Sorbitans• Triazines
Yes
No
Yes
R 394
E 353 H 524
CC
T 347
AA BB
““B_site only” Interaction B_site only” Interaction
H3C
NH2
ChemicalInventory
Contains CycleYes Contains 2 OH,
or OH and =0, at Spec. Dist
Possible High Affinity,“A-B”; “A-C”; or
“A-B-C” type binder
Contains some attenuating feature
steric?; other?
High Binding Affinity “A-B”;“A-C” or “A-B-C” type
No
Non binder Ex: ProgesteroneCorticossterone(RBA<0.00001)
Log Kow <1.3
Low Affinity Binder“A-B”,“A-C” or “A-B-C” type
Assess strength of attenuation steric?;
other?
Some
Complete
Contains at least
one possible
H-bonding site
Type “A”Contains Phenol
Fragment
• Alkyl Anilines• Phthalates• Branched Phenones• Cyclo Phenones• p-subst Cyclohexanols• p-subst Cyclohexanones• ring subst (o-CH3, tri-CH3) Benzoates
V
Possible Low AffinityBinder
Type “B”Contains identif. Type B
Fragment
• N-alkyl Phenones• Non ring subst Benzoates
• Alkyl Phenols • Alkoxy Phenols• Parabens• Salicylates
Belongs to known Active
class
Potency Rules / Equations
Potency Rules / Equations
No
Yes No
No
II
Needs testing
Yes
No
No
Yes
Yes
Belongs to class with possible
Type B low affinity under investigation
Belongs to known Inactive
class
IIIBelongs to
known Inactive class
• Fully-hindered Alkyl Phenols
Belong to untested classwith possible
Type A low affinity
• ring subst p-CH3 Benzoates •Thiophosphate Esters• Mixed Organics• Cyclic Alcohols (not p-subst hexanols)• Cyclic Pentanones/Others• Br, I halobenzenes
No
No
Yes
Belongs to known Active
class
Belong to untested class
Needs testing
Needs testing
Non binder(RBA<0.00001)
• Mixed Phenols
No
No
No
Yes
Yes
YesIII
Non binder(RBA<0.00001)
No
Belongs to known Inactive
class
Non binder(RBA<0.00001)
• Alkylbenzsulfonic Acids• Sulfonic Acid Dyes• p-Alkyl Fluorobenzenes• Bis–anilines• Alkoxy Anilines• Imidazolidines• Isothiazolines• Alkyl Benzthiols• Pyrrolidiones
Yes
• Oxazoles• Benzamide• Furans• Sorbitans• Triazines
Yes
Yes
No
Yes
5.12 calc.
CH3
NH2
2.70 msrd
CH3
CH3
CH3
NH2NH2
CH3
1.96 msrd
Alkyl Anilines
2.47 msrd 6.82 msrd 2.83 msrd 4.91 msrd
O
O
O
CH3
CH3
O
CH3
CH3
O
O
O
CH3
O
CH3 O
O
O
O
CH3
O
O
O
CH3
O
CH3
Phthalates
3.07 calc.3.00 msrd2.73 msrd
CH3 CH3
CH3
OO
CH3
CH3
O
CH3
CH3
Branched Phenones
ChemicalInventory
Contains CycleYes Contains 2 OH,
or OH and =0, at Spec. Dist
Possible High Affinity,“A-B”; “A-C”; or
“A-B-C” type binder
Contains some attenuating feature
steric?; other?
High Binding Affinity “A-B”;“A-C” or “A-B-C” type
No
Non binder Ex: ProgesteroneCorticossterone(RBA<0.00001)
Special Rule Classes
Log Kow <1.3
Low Affinity Binder“A-B”,“A-C” or “A-B-C” type
Assess strength of attenuation steric?;
other?
Some
Complete
Contains at least
one possible
H-bonding site
Type “A”Contains Phenol
Fragment
• Alkyl Anilines• Phthalates• Branched Phenones• Cyclo Phenones• p-subst Cyclohexanols• p-subst Cyclohexanones• ring subst (o-CH3, tri-CH3) Benzoates
V
Possible Low AffinityBinder
Type “B”Contains identif. Type B
Fragment
• N-alkyl Phenones• Non ring subst Benzoates
• Alkyl Phenols • Alkoxy Phenols• Parabens• Salicylates
Belongs to known Active
class
Potency Rules / Equations
No
Potency Rules / Equations
No
Yes No
No
II
Needs testing
Yes
No
No
Yes
Yes
Belongs to class with possible
Type B low affinity under investigation
Belongs to known Inactive
class
IIIBelongs to
known Inactive class
• Fully-hindered Alkyl Phenols
Belong to untested classwith possible
Type A low affinity
• ring subst p-CH3 Benzoates•Thiophosphate Esters• Mixed Organics• Cyclic Alcohols (not p-subst hexanols)• Cyclic Pentanones/Others• Br, I halobenzenes
No
No
Yes
Belongs to known Active
class
Belong to untested class
Needs testing
Needs testing
Non binder(RBA<0.00001)
• Mixed Phenols
No
No
No
Yes
Yes
YesIII
Non binder(RBA<0.00001)
No
Belongs to known Inactive
class
Non binder(RBA<0.00001)
• Alkylbenzsulfonic Acids• Sulfonic Acid Dyes• p-Alkyl Fluorobenzenes• Bis–anilines• Alkoxy Anilines• Imidazolidines• Isothiazolines• Alkyl Benzthiols• Pyrrolidiones
IV
Yes
• Oxazoles• Benzamide• Furans• Sorbitans• Triazines
Yes
Yes
No
Yes
• DDT-Like• Tamoxifen-Like• Multi-Cyclohydrocarbons• Alkyl Chlorobenzenes
5.87 calc. 3.30 msrd
Multi-Cyclic Hydrocarbons
Cl
CH3
4.94 calc.
Cl
CH3
4.41 calc.3.88 calc. 5.47 calc.
Cl
CH3
Cl
CH3
Alkyl-Chlorobenzenes
Cl
O
N
CH3
CH3
OHO
OH
O
OH
O
OH
6.89 calc.4.03 msrdCH3
N
CH3O
CH3
Tamoxifen Like
6.53 calc.
ClCl
ClCl
Cl
DDT Like
Setting Priority for Further Testing: Food Use Inert and Antimicrobial Lists
Lower Priority if: -Chemical belongs to a class where testing showed no evidence of ER interaction (RBA < 0.00001); -LogP <1.3, or meets other class specific LogP cutoffs
General characteristics of these chemicals: -Acyclic (e.g., no benzene rings)-Cyclic but does not contain a likely H-bonding group;
RBA = relative binding affinity; (a ratio of measured chemical affinity for the ER relative to 17-beta-Estradiol = 100%)Log P = log of octanol/water partition coefficient (also known as Log Kow); is an indicator of lipophilicity
Setting Priority for Further Testing: Food Use Inert and Antimicrobial Lists
Higher Priority if: -Chemical belongs to class with evidence of ER interaction, and:-LogP > 1.3 (or other class-specific cutoffs)
General characteristics of these chemicals: -Contains at least one cycle (e.g., benzene ring);-Contains a possible H-bonding group;
Inactive Classes – Lower PriorityInactive Classes FI AMAcyclics 230 122Alkylbenzenesulfonic Acids 78 3Sulfonic Acid Dyes 9 1Sorbitans 7 0Monocyclic Hydrocarbons 7 0Cyclic caged Hydrocarbon 1 0Pyrrolidines 3 0Furans 3 0N-chain Phenones 1 0Oxazoles 0 3Triazines 1 13Isothiazolines 3 7Imidazolidines 0 8Cyclic Inorganics 0 3Fully-Hindered Alkylphenols 1 0Cyclic Pentanones/Others 2 0Inactive ranges in Otherwise Positive ClassesCyclic Hexanones of LogP<1.5 1 0Cyclic Hexanols of LogP<1.5 1 0Chlorobenzenes of LogP<4 1 0Inactives in Mixed Functional Grps/Heteratom ClassesMixed Phenols 4 1Mixed Organics 14 13Organometallics 0 1
Total Inactives 367 175
1.50 msrd 1.97 msrd 2.47 msrd 3.65 msrd 3.20 msrd
OHCH3 OH
CH3
OHOH
CH3
OH
CH3
Classwise Differences in Lower LogKow Cutoff
p-n-Alkyl Phenols
AlkylAnilines
NH2
0.90 msrd 3.05 msrd
NH2
CH3
1.96 msrd
NH2
CH3
2.40 msrd
CH3 NH2
1.39 msrd
CH3
NH2
p-n-Alkyl Anilines
Cl
2.84 msrd 4.41 calc. 3.88 calc.
Cl
CH3
Cl
CH3
Cl
CH3
4.94 calc.
p-n-Alkyl Chloro
benzenes
OH
1.23 meas
n-Alkyl Cyclo
hexanols
2.32 calc.
OH
CH3
3.37 calc.
OH
CH3
Active Classes – High PriorityActive Classes FI AMAlkyl Phenols 4 9Parabens 3 0Salicylates 1 0Phthalates 3 0Actives in Mixed Functional /Heteratom ClassesMixed Phenols 1 6Mixed Organics 1 0
Total Positives 13 15
Classes – Under InvestigationClasses FI AMMixed Phenols (?) 3 2Mixed Organics (?) 7 16Organometallics (?) 2 3Thiophosphate Esters (?) 1 0
Total Under Investigation 13 21
Inventory Status – September 20, 2007
Food Use Inventory Antimicrobials
393 Total Chemicals 211
367 (94%) Lower Priority 175 (82%)
13 ( 3%) Higher Priority 15 ( 7%)
13 ( 3%) Under Investigation 21 (10%)
Summary of Current FindingsFood Use Inert and Antimicrobial Lists
ChemicalInventory
Contains CycleYes Contains 2 OH,
or OH and =0, at Spec. Dist
Possible High Affinity,“A-B”; “A-C”; or
“A-B-C” type binder
Contains some attenuating feature
steric?; other?
High Binding Affinity “A-B”;“A-C” or “A-B-C” type
No
Non binder Ex: ProgesteroneCorticossterone(RBA<0.00001)
Special Rule Classes
Log Kow <1.3
Low Affinity Binder“A-B”,“A-C” or “A-B-C” type
Assess strength of attenuation steric?;
other?
Some
Complete
Contains at least
one possible
H-bonding site
Type “A”Contains Phenol
Fragment
• Alkyl Anilines• Phthalates• Branched Phenones• Cyclo Phenones• p-subst Cyclohexanols• p-subst Cyclohexanones• ring subst (o-CH3, tri-CH3) Benzoates
V
Possible Low AffinityBinder
Type “B”Contains identif. Type B
Fragment
• N-alkyl Phenones• Non ring subst Benzoates
• Alkyl Phenols • Alkoxy Phenols• Parabens• Salicylates
Belongs to known Active
class
Potency Rules / Equations
No
Potency Rules / Equations
No
Yes No
No
II
Needs testing
Yes
No
No
Yes
Yes
Belongs to class with possible
Type B low affinity under investigation
Belongs to known Inactive
class
IIIBelongs to
known Inactive class
• Fully-hindered Alkyl Phenols
Belong to untested classwith possible
Type A low affinity
• ring subst p-CH3 Benzoates•Thiophosphate Esters• Mixed Organics• Cyclic Alcohols (not p-subst hexanols)• Cyclic Pentanones/Others• Br, I halobenzenes
No
No
Yes
Belongs to known Active
class
Belong to untested class
Needs testing
Needs testing
Non binder(RBA<0.00001)
• Mixed Phenols
No
No
No
Yes
Yes
YesIII
Non binder(RBA<0.00001)
No
Belongs to known Inactive
class
Non binder(RBA<0.00001)
• Alkylbenzsulfonic Acids• Sulfonic Acid Dyes• p-Alkyl Fluorobenzenes• Bis–anilines• Alkoxy Anilines• Imidazolidines• Isothiazolines• Alkyl Benzthiols• Pyrrolidiones
IV
Yes
• Oxazoles• Benzamide• Furans• Sorbitans• Triazines
Yes
Yes
No
Yes
• DDT-Like• Tamoxifen-Like• Multi-Cyclohydrocarbons• Alkyl Chlorobenzenes
• Alkyl Anilines• Phthalates• Branched Phenones• Cyclo Phenones• p-subst Cyclohexanols• p-subst Cyclohexanones• ring subst (o-CH3, tri-CH3) Benzoates
Type “B”Contains identif. Type B
Fragment
• N-alkyl Phenones• Non ring subst Benzoates
Potency Rules / Equations
Yes
Belongs to class with possible
Type B low affinity under investigation
Belongs to known Inactive
class• ring subst p-CH3 Benzoates•Thiophosphate Esters• Mixed Organics• Cyclic Alcohols (not p-subst hexanols)• Cyclic Pentanones/Others• Br, I halobenzenes
No
Belongs to known Active
class
Needs testing
No
Yes
Yes
III
Non binder(RBA<0.00001)
3.84 msrd 3.59 msrd 4.15 msrd 4.01 msrd 3.84 msrd
O
O
CH3
O
O CH3
CH3
O
O
CH3
O
O
O
O
Non Ring-subst. Benzoates
3.61 calc. 3.69 msrd 4.14 calc.
O
CH3
CH3
CH3
O CH3
O
OH
CH3
CH3
CH3
O
CH3
CH3
CH3
O
CH3
Ring-subst. (tri-CH3) Benzoates
2.64 msrd
O
CH3
O
CH3
O
CH3
O
CH3
2.75 msrd
Ring-subst. (o-CH3) Benzoates
O
CH3
O
CH3
2.75 msrd
Ring-subst. (p-CH3) Benzoates
2.47 msrd
O
O
O
CH3
O
CH3
Phthalate
Summary• The decision support system has been coded to perform
an automatic classification of discrete chemical inventories.
• Modifications to the decision tree are made as needed as new inventories are examined which contain new structure/activity classes
• Decision support system was designed to categorize chemicals with similar activity (ER binding potential) to determine common aspects of structure.
AcknowledgementsEPA Mid-Continent Ecology Divivsion-Duluth:
Pat Schmieder, Mark Tapper, Jeff Denny, Barb Sheedy, Mike Hornung, Hristo Aladjov
Student Services Contractors:Carlie Peck, Beth Nelson, Tori Wehinger, Ben Johnson,
Luke Toonen, Rebecca Maciewski, Will Backe, Melissa Dybvig, Megyn Mereness
International QSAR Foundation:Gil Veith
EPA Office of Pesticide Programs:Steve Bradbury, Jonathan Chen, Jean Holmes, Kerry Leifer,
Betty Shackleford, Najim Shamim, Deborah Smegal, Pauline Wagner
OASIS software (Laboratory of Mathematical Chemistry): Bourgas, Bulgaria – Ovanes Mekenyan