Exploiting In Silico Techniques for Human Phase I Metabolism Prediction with...
Transcript of Exploiting In Silico Techniques for Human Phase I Metabolism Prediction with...
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Gabriele Cruciani, Perugia University
Exploiting In Silico Techniques for Human Phase I
Metabolism Prediction with SmartphoneGabriele Cruciani, University of Perugia
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Gabriele Cruciani, Perugia University
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Gabriele Cruciani, Perugia University
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.
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Gabriele Cruciani, Perugia University
DRUG-impurities
Foodingredients-
toxins
Detergents
METABOLITES
WANTED EFFECTS
UNWANTED EFFECTS
ADME
Tox
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Gabriele Cruciani, Perugia University
DRUG-impurities
Foodingredients-
toxins
Detergents
METABOLITES
WANTED EFFECTS
UNWANTED EFFECTS
ADME
QSPR
Tox
Chemical description
01100011100010101
Identification
of metabolites
chemical structure
abundance, kinetics
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Gabriele Cruciani, Perugia University
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
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Gabriele Cruciani, Perugia University
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
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Gabriele Cruciani, Perugia University
Full MetID - 20 compounds/day (report included)
30min | 15min | 2min |
Semi-automatised procedure for MetID profiling
Today MetID – the HITROXEN approach
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Gabriele Cruciani, Perugia University
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
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Gabriele Cruciani, Perugia University
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°
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Gabriele Cruciani, Perugia University
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
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Gabriele Cruciani, Perugia University
Biotransformations (in silico) of ML3403
P450
FMO
AOX
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Gabriele Cruciani, Perugia University
Potential biotransformations (in silico) of MC041
P450
FMO
AOX
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Gabriele Cruciani, Perugia University
Exp. biotransformations (in silico) of MC041
P450
FMO
AOX
1
2
3
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Gabriele Cruciani, Perugia University
MC041
Metabolism of MC041
Amides
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Gabriele Cruciani, Perugia University
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
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Gabriele Cruciani, Perugia University
The growing complexity
Holistic approachNot 6-dimensional … but still dimensionally demanding
Conclusions
ligan
ds-
pro
t
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Gabriele Cruciani, Perugia University
Background
30 ns
6 weeks GPU
1tqn holo
16000 wat
35 wat
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Gabriele Cruciani, Perugia University
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
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Gabriele Cruciani, Perugia University
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
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Gabriele Cruciani, Perugia University
Ser271
Glu189
2D representation of CYP 2D6 active site
MetaSite approach
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Gabriele Cruciani, Perugia University
Ser271
Glu189
2D representation of CYP 2D6 active siteMetaSite approach
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Gabriele Cruciani, Perugia University
Ser271
Glu189
MetaSite approach
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5 4a
+
electrophile
human FMO3
O2
O
HEME
radical
CYP450 FMOx AOX
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Gabriele Cruciani, Perugia University
CYPs reactivity module
MetaSite reactivity
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Gabriele Cruciani, Perugia University
prediction for 150 new fragments
S
Nucleophilic scale
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Gabriele Cruciani, Perugia University
Porting to android and iOS
client-server application:Calculations are performed on a cloud or remote server
Chemodrome android