gabriele cruciani, laura goracci - unipr.it · efsa parma, 11-13 june 2019 gabriele cruciani...

Gabriele CrucianiEFSA Parma, 11-13 June 2019

Gabriele Cruciani, Laura GoracciDepartment of Chemistry, Biology and Biotechnology, University of Perugia, Italy

& Molecular Discovery, London

Photos from Perugia, Umbria, Italy

Risks & benefits of the use of computational methods

Parma Summer School 2019 EFSA Parma, 11-13 June 2019


Outline

1. Approaches for structure-property relationships

2. Limits of QSAR (QSPR) methods

3. Phenotype descriptors using –omics approach

4. Examples


DRUG-impurities

Foodingredients-

toxins

Detergents

Tox

UNWANTED EFFECTS

1st approach: Structure-Property Relationships

Risk-benefit assessment of medicinal products (A. Kouroumalis)


DRUG-impurities

Foodingredients-

toxins

Detergents

Tox

UNWANTED EFFECTS


xenobiotics

Chemical description01100011100010101



DRUG-impurities

Foodingredients-

toxins

Detergents

Tox

UNWANTED EFFECTS

QSPR


xenobiotics




DRUG-impurities

Foodingredients-

toxins

Detergents

Tox

UNWANTED EFFECTS

QSPR


AI

xenobiotics



DRUG-impurities

Foodingredients-

toxins

Detergents

Tox

xenobiotics

UNWANTED EFFECTS

METABOLITES

Phase I metabolites

Phase II metabolites

Kinetics

2nd approach: Structure-Property Relationships

Chemical descriptions01100011100010101

hitroxen


DRUG-impurities

Foodingredients-

toxins

Detergents

Tox

xenobiotics

UNWANTED EFFECTS

METABOLITES

Phase I metabolites

Phase II metabolites

Kinetics

3rd approach: Structure-Property Relationships

phenotype description01100011100010101

METABOLOMICS

LIPIDOMICS

organoids


noTox Tox

example


o

Troglitazone

Hepatotoxic

Pioglitazone Thiazolidinediones tox pathway:

Oxidative CYP3A4Kassahun et. al. Chem. Res. Toxicol.

(14), 62-70, 2001


Pioglitazone Troglitazone12 days human MIT hepatocye


PioglitazoneTroglitazone12 days human MIT hepatocyte


Tamoxifen DILI+(Steatohepatitis)

Benefit: prevent breast cancer

Risk: increased risk of uterine cancer, stroke

Risk / Benefit ??

Personalised approach


564,2558

Medium

563,2183

Medium

358,2353

Medium

& lipids

374,2368

Medium

medium

374,2368

Medium

lipids

Ultra fast automatic MetID

& lipidomic for phenotypic

fingerprint


2 days4 days6 days8 days11

days

14 days

LipoTox Technology Platform


Tamoxifen DILI+(Steatohepatitis)

Toxicity increases


• Analyze overall toxicity profiles• Profile characteristics

• Unsupervised and supervised approaches to compare profiles

• Focus on individual endpoints• Correlate to external data

• Build an understanding of clinical mechanisms

23

What Can We Do With LipoTox Profile Data?


• Compound characterization

• ADME Property profiles

• Pathways, possible clinical indications

• Mechanism of action

• Unexpected off-targets (toxicity)

• Support therapeutic hypotheses

• Compare to competitor molecules, clinical standards of care

• Identify translational biomarkers

24

Applications


• Challenges for studying drug combinations:

• System may include more drugs

• Suitably robust to capture combination effects

25

Drug Combinations


MALDI (DESI) Metab-Lipid-omics (looking for locations in space)


Alessandra Di Veroli

Aurora Valeri

Fabien Fontain

Laura Goracci

Massimo Baroni

Paolo Benedetti

Paolo Tiberi

Sara Tortorella

Stefano di Bona

Molecular Discovery

Thanks to …


Rosso di sera .. bel tempo si spera !!

Red sky at night, shepherd’s delight

Thanks all …

gabriele cruciani, laura goracci - unipr.it · efsa parma, 11-13 june 2019 gabriele cruciani...

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