Exploiting In Silico Techniques for Human Phase I Metabolism Prediction with Smartphonefiles.moldiscovery.com/GabrieleCruciani_CPSA2016.pdf · 2016. 10. 14. · Gabriele Cruciani,

Gabriele Cruciani, Perugia University

Exploiting In Silico Techniques for Human Phase I

Metabolism Prediction with SmartphoneGabriele Cruciani, University of Perugia



How does the body protect itself against xenobiotics ?

A xenobiotic is a chemical which is found in an organismbut which is not normally produced or expected to be present in it

• By preventing xenobioticsfrom entering into the bloodstrem or organs

Absorption or Distribution

• By physical elimination Excretion

• By chemical elimination Metabolism =

biotransformation

The xenobiotic is transformed in the body into products

(metabolites) which are usually more water-soluble and easier

to excrete.


DRUG-impurities

Foodingredients-

toxins

Detergents

METABOLITES

WANTED EFFECTS

UNWANTED EFFECTS

ADME

Tox


DRUG-impurities

Foodingredients-

toxins

Detergents

METABOLITES

WANTED EFFECTS

UNWANTED EFFECTS

ADME

QSPR

Tox

Chemical description

01100011100010101

Identification

of metabolites

chemical structure

abundance, kinetics


P450 enzymes are not new entities in organic synthesis

Example: in sterol biosynthesis P450 can oxidise unreactive methyl groups in the presence of double bonds

Lanosterol Ergosterol conversion


Metabolomics/lipidomics signal interpretation

WARNINGS TOO GOOD!...DRUG METABOLITES EFFECT(lipid impairment associated to drugs)

Cell treated with drug 1Cell treated with drug 2

METAB DRUG 1 METAB DRUG 2

DEDICATED SOFTWARES FOR UNTARGETED LIPIDOMICS


Full MetID - 20 compounds/day (report included)

30min | 15min | 2min |

Semi-automatised procedure for MetID profiling

Today MetID – the HITROXEN approach


Phase I & II metabolismPropranolol -> several metabolites

O NH2

OH

O NH

OH

OH

O NH2

OH

OH

O

OH

CHO

O OH

OH

O

OH

COOH

O

OH

COOH

OH

O OH

OH

OH

O COOH

O NH

OH

1

O NH

OH

HO

NH2

GLUC

SULF

GLUC

GLUC

GLUC

GLUC

SULFGLUC

SULF

GLUC

GLUC

SULF

OCH3

Phase I metabolism by CYPs


O NH2

OH

O NH

OH

OH

O NH2

OH

OH

O

OH

CHO

O OH

OH

O

OH

COOH

O

OH

COOH

OH

O OH

OH

OH

O COOH

O NH

OH

1

O NH

OH

HO

NH2

GLUC

SULF

GLUC

GLUC

GLUC

GLUC

SULFGLUC

SULF

GLUC

GLUC

SULF

OCH3

Phase I & II metabolismPropranolol -> several metabolites

1°

2°

3°


O NH2

OH

O NH

OH

OH

O NH2

OH

OH

O

OH

CHO

O OH

OH

O

OH

COOH

O

OH

COOH

OH

O OH

OH

OH

O COOH

O NH

OH

1

O NH

OH

HO

NH2

GLUC

SULF

GLUC

GLUC

GLUC

GLUC

SULFGLUC

SULF

GLUC

GLUC

SULF

OCH3

Phase I & II metabolismPropranolol -> 21 metabolites


Biotransformations (in silico) of ML3403

P450

FMO

AOX


Potential biotransformations (in silico) of MC041

P450

FMO

AOX


Exp. biotransformations (in silico) of MC041

P450

FMO

AOX

1

2

3


MC041

Metabolism of MC041

Amides


PSoMi = [(1+we) • Ei] • [(1+wr) • Ri]

Exposure of

reactive atom to

reactive center

Heme, FAD, Mo

Cu++ …..Atom reactivity

(RAE, nucleofilicity,

elettrofilicity …)Cruciani et al., J.Med.Chem, 2014


The growing complexity

Holistic approachNot 6-dimensional … but still dimensionally demanding

Conclusions

ligan

ds-

pro

t


Background

30 ns

6 weeks GPU

1tqn holo

16000 wat

35 wat


MetaSite 5.0

New reactivity and exposure integrated

Results (on compounds with well-known metabolite ranking)

st. validation method new validation method(top three solutions) (precise ranking)

2D698% correct solutions 80% correct solutions

2C996% correct solutions 78% correct solutions

3A494% correct solutions 75% correct solutions

MetaSite: the new performance scale


MetaSite 5.0

Results (on compounds with well-known metabolite ranking)

st. validation method new validation method(top three solutions) (precise ranking)

FMO100% correct solutions 95% correct solutions

AOX100% correct solutions 95% correct solutions

Substrate selectivity

FMO82% correct solutions

AOX85% correct solutions


Ser271

Glu189

2D representation of CYP 2D6 active site

MetaSite approach


Ser271

Glu189

2D representation of CYP 2D6 active siteMetaSite approach


Ser271

Glu189

MetaSite approach

5 4a

+

electrophile

human FMO3

O2

O

HEME

radical

CYP450 FMOx AOX


CYPs reactivity module

MetaSite reactivity


prediction for 150 new fragments

S

Nucleophilic scale


Porting to android and iOS

client-server application:Calculations are performed on a cloud or remote server

Chemodrome android


[email protected]

[email protected]

Thanks

Documents

Exploiting In Silico Techniques for Human Phase I Metabolism Prediction with Smartphonefiles.moldiscovery.com/GabrieleCruciani_CPSA2016.pdf · 2016. 10. 14. · Gabriele Cruciani,