AN IN SILICO APPROACH TO ENDOCRINE DISRUPTORS: THE MOLECULAR MODELLING...

EFSA ndash IPAM day

3rd LIFE-EDESIA workshop on

Endocrine Disruptors and alternative methods to animal testing - a scientific and regulatory perspective

Parma (I) 28022018

Endocrine Disruptors and the in vitro alternative methods to animal testing

Molecular Modelling Lab

Food amp Drug Department

University of Parma

AN IN SILICO APPROACH

TO ENDOCRINE DISRUPTORS

THE MOLECULAR MODELLING VIEW

Pietro Cozzini

TOO MANY CHEMICALS EVERY YEARImpossible to test in a wet lab

AIM To borrow drug design techniques for food science

Many compounds of interest for food science are able to mimic endogenous molecules

Toxins

Food

additivesNatural compounds

Industrial or packaging

contaminants

Many proteic targets has been identifiedhelliptoo much to be identified

AIM To predict the energy interaction between a small molecule and a large protein

TARGET STRUCTURE

LIGANDSTRUCTURES

LIGAND BASED SCREENINGQSAR

HTPSCOMBICHEM

NO

YESNO

A MOLECULAR MODELLING FLOW CHART

TARGET STRUCTURE

LIGANDSTRUCTURES

STRUCTURE BASED DRUG DESIGN

DE NOVODESIGN

YES

YESNO

The Lock and Key model (and the Locksmith)

+

FAST amp CHEAP

IN SILICO

IN VITRO

IN VIVO

Thousandhelliphelliphelliphellip

Millions

Tens

Few units

Food Chem Toxicol2008 Mar46 Suppl 1S2-70 doi 101016jfct200802008Safety and nutritional assessment of GM plants and derived food and feed the role of animal feeding trialsEFSA GMO Panel Working Group on Animal Feeding Trials

STRUCTURE SOURCES

X-RAY and NEUTRON DIFFRACTION

NMR

HOMOLOGY MODELLING

X-ray diffraction

Neutron diffraction

NMR

Homology Modelling

Resolution value

Atom and Bond types attribution

Hydrogens position

Water orientation

Differences between crystallization pH

and Ki determination pH

Incompatibility between different

molecular modelling programs (SYBYL

Insight MacroModelhellip)

difficulties

STRUCTURAL DATA BE CAREFUL

TECHNIQUES STRUCTURAL LIMITS

THE DOCKING PROBLEM

HOW CAN WE BUILD RELIABLE MODELS AND OBTAIN GOOD PREDICTION IN TIME

Positioning a geometryproblem

Evaluation energy a chemistryproblem

ScreeningDocking engine Fast Scoring Function

UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based

Docking and Consensus Scoring (Re-scoring)

GOLD HINT

Our computational approach

FLAP amp GRID approach

3D DB

TOOLS

Ligand and Binding Site

Structure Analisys

Virtual screening

Dockingscoring simulations

Re-scoring procedure

GOLD (Parma)

LIFE EDESIA

HINT(Hydropathic INTeractions)

HINT empirical scoring function based on experimental LogPow

values

MOLEGRO MolDock (Etnalead)

Another definition of a docking machine

(for someone)

NO

Unsuccesfull dockings

PDB protein ligand failure

1aaq HIV-1 protease Hydroxyethylene isostere Very flexible ligand

1rne renin CGP38560 Very flexible ligand

1poc Phospholipase A2 phosphoenolamine Very flexible ligand

1lic LBP Hexadecanesulfonic acid Very flexible ligand

1eed endothiapepsin PD125754 Very flexible ligand

1eap Catalytic antibody phosphonate

Flexible ligand

symmetrical distribution of

apolar groups

1glqGlutathione

transferaseglutathione Partially buried ligand

1mer IGD light chain N-acetyl-L-His-D-Pro-Oh OpenShallow active site

1ghb Chymotrypsin N-acetyl D-Trp Short intemolecular dist

1ive Neuroaminidase Aminobenzoic acid Short intemolecular dist

Kellenberger et al PROTEINS 57225-242 (2004)

Docking Results Accuracy

IFthe interaction is predicted positive

THENthe compounds should be subjected to further experimental trials

ELSE IFthe prediction is negative

THENfurther experiments should be carried on in order to verify the strength of the technique improve

method and deeply understand molecular mechanisms of bindingactivity

ENDIF

CASE STUDIESdrugs food or contaminants it is always chemistry

drug molecules or food molecules could act as xenoestrogens

VALIDATION OF AN ldquoIN SILICOrdquo METHOD FOR THE SCREENING

OF THE INTERACTION BETWEEN ESTROGEN RECEPTORS

ALPHA AND FOOD MOLECULES

The method resulted highly predictive for Parabens and PCBs (074 and 065 r2 respectively)

and alkylphenols (r2 042 and a 71 success rate)

DB of 126 ligands

SCREENING OF FOOD POLLUTANTS

493 compounds

53 choosen

37 analized

13 potential xenoestrogens

1500 compounds

Database developed from JEFCA and EAFUS(Joint FAOWHO Expert Committee on Food additives and Evrythings Addes to the Food in

USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α

LIFEEDESIA NUCLEAR RECEPTORS

Macro Flexibility αER-LBD

Active Inactive

OPEN

(ANTAGONIST)CONFORMATION

CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524

How many conformations of the

receptor two or more

Testo

LOCAL FLEXIBILITY HIS 524

Even if a docking program could easily find an accurate

pose for a ligand accurate ranking sometimes remains

an issue

moreoverhellip

Docking Problems and Limits

Impossible simulation of covalent interactions formation

and breaking

Difficult evaluation of water molecules contribution

High MW ligands are difficult to dock

High percentage of false-positive results in virtual

screening

LIFE EDESIA

SCREENINGQSAR DBASE Literature

DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA

Consensus Docking Report

bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS

LIFE EDESIA SCREENING

Bisphenols

Common Name ER ER ARwt ARmut

HTMD HTMD HTMD HTMD

Bisphenol A YES - YES- YES - Maybe -

bisphenol AF YES YES YESYES YES NO NO NO

bisphenol AP YES YES YESYES NO NO Maybe Maybe

BADGE NO NO NO NO Maybe YES YESYES

BFDGE NO NO NO NO Maybe Maybe YESYES

Pergafast201 NO NO NO NO NO NO NO NO

BisOPP-A NO NO NO NO NO NO NO

TGSA NO NO NO NO NO NO NO NO

MBHA YES YES YESYES Maybe Maybe Maybe YES

S-24-bisphenol YES YES YESYES NO NO NO NO

Bisphenol F YES YES YESYES Maybe YES NO NO

BPS-MPE NO YES NO YES NO NO NO NO

Bisphenol C NO NO NO NO Maybe NO YESMaybe

BPS NO NO NO NO NO NO NO NO

17-Bis(4-hydroxyphenylthio)-

35-dioxaheptane NO NO NO NO Maybe YES Maybe NO

D8 NO YES NO YES NO NO Maybe Maybe

BPS-MAE NO NO NO NO NO NO Maybe YES

rarr indicates incongruence of prediction between docking methods

LIFE EDESIA RESULT(Unpublished data)

Now we are ready for in vitro testsin a wet lab

EFSA ndash IPAM day



Parma (I) 28022018


THANK YOU FOR YOUR ATTENTION

CAS Common name Chemical class

117-81-7 DEHP Phtalates

100-97-0 hexamethylenteramine Miscellaneous

102-76-1 glyceryl triacetate Miscellaneous

103-23-1 diethylhexyladipate Miscellaneous

105-08-8 CHDM Miscellaneous

105-99-7 DBA Miscellaneous

110-17-8 fumaric acid Acids

110-44-1 sorbic acid Acids

120-61-6 DMTP Phtalates

122-62-3 dioctylsebacate Miscellaneous

1241-94-7 DEHPA Phtalates

128-37-0 BHT Phtalates

1478-61-1 bisphenol AF Bisphenols

151882-81-4 BTUM Miscellaneous

1571-75-1 bisphenol AP Bisphenols

166412-78-8 DINCH Phtalates

1675-54-3 BADGE Bisphenols

2095-03-6 BFDGE Bisphenols

232938-43-1 Pergafast201 Bisphenols

24038-68-4 BisOPP-A Bisphenols

28553-12-0 Di-isononyl phthalate Phtalates

3010-96-6 CDBO Miscellaneous

3319-31-1 TEHTM Phtalates

3380-34-5 Triclosan Parabens

41481-66-7 TGSA Bisphenols

5129-00-0 MBHA Bisphenols


52-51-7 bronopol Miscellaneous

5397-34-2 S-24-bisphenol Bisphenols

55-56-1 Chlorhexidine Miscellaneous

620-92-8 bisphenol F Bisphenols

63134-33-8 BPS-MPE Bisphenols

6422-86-2 DOTP Phtalates

65-85-0 Benzoic_acidbenzoate Acids

67-63-0 isopropyl alcohol Miscellaneous

6915-15-7 malic acid Acids

77-90-7 Acetyltributylcitrate Miscellaneous

78-42-2 TEHPA Miscellaneous

79-09-4 propionic acid Acids

79-97-0 bisphenol C Bisphenols

80-05-7 Bisphenol A Bisphenols

80-09-1 S-44-bisphenol (BPS) Bisphenols

82469-79-2 BTHC Miscellaneous

84-66-2 DEP Phtalates

84-69-5 Diisobutylphthalate Phtalates

84-74-2 Di-buthyl phtalate Phtalates

84-77-5 Di-n-decyl phthalate Phtalates

88-19-7 OTSA Miscellaneous

93589-69-6 17-Bis(4-hydroxyphenylthio)-35-dioxaheptane Bisphenols

94-13-3 Propyl paraben Parabens

94-18-8 PHB Parabens

95235-30-6 D8 Bisphenols

97042-18-7 BPS-MAE Bisphenols

99-76-3 Methyl paraben Parabens

methylmaltoside methyl_maltoside Sugars

Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates


HINTMolD HINTMolD HINTMolD HINTMolD

DEHP NO - NO - NO - NO -

DEP NOsect - NOsect - NO - NO -

Diisobutylphthalate NO - NO - NO - NO -

DEHPA NO NO NO NO NO NO NO NO

BHT NO NO NO NO NO NO NO NO

DINCH NO NO NO NO NO NO NO NO

Di-isononyl phthalate NO NO NO NO NO NO NO NO

TEHTM NO NO NO NO NO NO NO NO

DOTP NO NO NO NO NO NO NO NO

DMTP NO NO NO NO NO NO NO NO

Di-buthyl phthalate NOsect NO NOsect NO NO NO NO NO

Di-n-decyl phthalate NO NO NO NO NO NO NO NO

sect rarr NON agonistic activity cannot be excluded

Parabens


HTMD HTMD HTMD HTMD

Methyl paraben YES - YES- NO - NO -

Propyl paraben YES - YES- NO - NO -

Triclosan NO NO NO NO NO NO NO NO

PHB YES YES YESYES Maybe Maybe NO NO

Acids


HTMD HTMD HTMD HTMD

Benzoic acid NO NO NO NO NO NO NO NO

Sorbic acid NO NO NO NO NO NO NO NO

Propionic acid NO NO NO NO NO NO NO NO

Fumaric acid NO NO NO NO NO NO NO NO

Malic acid NO NO NO NO NO NO NO NO

Miscellaneous


HTMD HTMD HTMD HTMD

hexamethylenteramine NO NO NO NO NO NO NO NO

glyceryl triacetate NO NO NO NO NO NO NO NO

diethylhexyladipate NO NO NO NO NO NO NO NO

CHDM NO NO NO NO NO NO NO NO

DBA NO NO NO NO NO NO NO NO

dioctylsebacate NO NO NO NO NO NO NO NO

BTUM NO NO NO NO NO NO NO NO

CDBO NO NO NO NO NO NO NO NO

bronopol NO NO NO NO NO NO NO NO

Chlorhexidine NO NO NO NO NO NO NO NO

isopropyl alcohol NO NO NO NO NO NO NO NO

Acetyltributylcitrate NO NO NO NO NO NO NO NO

TEHPA NO NO NO NO NO NO NO NO

methylmaltoside NO NO NO NO NO NO NO NO

BTHC NO NO NO NO NO NO NO NO

OTSA NO NO NO NO NO NO NO NO

TOO MANY CHEMICALS EVERY YEARImpossible to test in a wet lab



Toxins

Food



contaminants



TARGET STRUCTURE

LIGANDSTRUCTURES


HTPSCOMBICHEM

NO

YESNO


TARGET STRUCTURE

LIGANDSTRUCTURES


DE NOVODESIGN

YES

YESNO


+

FAST amp CHEAP

IN SILICO

IN VITRO

IN VIVO


Millions

Tens

Few units


STRUCTURE SOURCES


NMR

HOMOLOGY MODELLING

X-ray diffraction

Neutron diffraction

NMR

Homology Modelling

Resolution value


Hydrogens position

Water orientation






difficulties



THE DOCKING PROBLEM





UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD



















Toxins

Food



contaminants



TARGET STRUCTURE

LIGANDSTRUCTURES


HTPSCOMBICHEM

NO

YESNO


TARGET STRUCTURE

LIGANDSTRUCTURES


DE NOVODESIGN

YES

YESNO


+

FAST amp CHEAP

IN SILICO

IN VITRO

IN VIVO


Millions

Tens

Few units


STRUCTURE SOURCES


NMR

HOMOLOGY MODELLING

X-ray diffraction

Neutron diffraction

NMR

Homology Modelling

Resolution value


Hydrogens position

Water orientation






difficulties



THE DOCKING PROBLEM





UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD


















TARGET STRUCTURE

LIGANDSTRUCTURES


HTPSCOMBICHEM

NO

YESNO


TARGET STRUCTURE

LIGANDSTRUCTURES


DE NOVODESIGN

YES

YESNO


+

FAST amp CHEAP

IN SILICO

IN VITRO

IN VIVO


Millions

Tens

Few units


STRUCTURE SOURCES


NMR

HOMOLOGY MODELLING

X-ray diffraction

Neutron diffraction

NMR

Homology Modelling

Resolution value


Hydrogens position

Water orientation






difficulties



THE DOCKING PROBLEM





UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















TARGET STRUCTURE

LIGANDSTRUCTURES


DE NOVODESIGN

YES

YESNO


+

FAST amp CHEAP

IN SILICO

IN VITRO

IN VIVO


Millions

Tens

Few units


STRUCTURE SOURCES


NMR

HOMOLOGY MODELLING

X-ray diffraction

Neutron diffraction

NMR

Homology Modelling

Resolution value


Hydrogens position

Water orientation






difficulties



THE DOCKING PROBLEM





UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD


















+

FAST amp CHEAP

IN SILICO

IN VITRO

IN VIVO


Millions

Tens

Few units


STRUCTURE SOURCES


NMR

HOMOLOGY MODELLING

X-ray diffraction

Neutron diffraction

NMR

Homology Modelling

Resolution value


Hydrogens position

Water orientation






difficulties



THE DOCKING PROBLEM





UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















FAST amp CHEAP

IN SILICO

IN VITRO

IN VIVO


Millions

Tens

Few units


STRUCTURE SOURCES


NMR

HOMOLOGY MODELLING

X-ray diffraction

Neutron diffraction

NMR

Homology Modelling

Resolution value


Hydrogens position

Water orientation






difficulties



THE DOCKING PROBLEM





UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















IN SILICO

IN VITRO

IN VIVO


Millions

Tens

Few units


STRUCTURE SOURCES


NMR

HOMOLOGY MODELLING

X-ray diffraction

Neutron diffraction

NMR

Homology Modelling

Resolution value


Hydrogens position

Water orientation






difficulties



THE DOCKING PROBLEM





UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















STRUCTURE SOURCES


NMR

HOMOLOGY MODELLING

X-ray diffraction

Neutron diffraction

NMR

Homology Modelling

Resolution value


Hydrogens position

Water orientation






difficulties



THE DOCKING PROBLEM





UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















X-ray diffraction

Neutron diffraction

NMR

Homology Modelling

Resolution value


Hydrogens position

Water orientation






difficulties



THE DOCKING PROBLEM





UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















THE DOCKING PROBLEM





UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD





















UNBOUND STATE

BOTH LIGAND AND

RECEPTOR ARE

SOLVATED AND DO NOT

INTERACT

BOUND STATE

LIGAND AND RECEPTOR

ARE PARTIALLY

DESOLVATED AND THEY

INTERACT WITH OR

WITHOUT THE SOLVENT

CONTRIBUTION

Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















Virtual Screening

Structure based

Ligand based


GOLD HINT



3D DB

TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















TOOLS


Structure Analisys

Virtual screening



GOLD (Parma)

LIFE EDESIA



values



(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD


















(for someone)

NO









Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

























Flexible ligand


apolar groups

1glqGlutathione












ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD























ENDIF








DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD






















DB of 126 ligands


493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD


















493 compounds

53 choosen

37 analized


1500 compounds


USA)

IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















IN VITRO TESTS

ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















ER-B

H12 H12

H12H12

AR PPAR

ER-Α



Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD


















Active Inactive

OPEN


CLOSE (AGONIST)

CONFORMATION

H12

H12

BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















BINDING SITE

bull Glu 353

bull Arg 394

bull Asp 351

bull His 524



Testo




an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD



















an issue

moreoverhellip



and breaking




screening

LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















LIFE EDESIA


DOCKINGSCORING

(54 CHEMICALS)

ER-a

ER-b

AR-wt

AR-mt

PARMACATANIA


bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















bull BISPHENOLS

bull PHTHALATES

bull PARABENS

bull ACIDS

bull MISCELLANEOUS


Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















Bisphenols


HTMD HTMD HTMD HTMD






















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD


















EFSA ndash IPAM day



Parma (I) 28022018



























































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD









































































Bisphenols


HTMD HTMD HTMD HTMD




















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















Phthalates
















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















Parabens


HTMD HTMD HTMD HTMD





Acids


HTMD HTMD HTMD HTMD






Miscellaneous


HTMD HTMD HTMD HTMD

















Miscellaneous


HTMD HTMD HTMD HTMD

















AN IN SILICO APPROACH TO ENDOCRINE DISRUPTORS: THE MOLECULAR MODELLING...

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Transcript of AN IN SILICO APPROACH TO ENDOCRINE DISRUPTORS: THE MOLECULAR MODELLING...