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

Gabriele CrucianiEFSA 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

Gabriele CrucianiEFSA Parma, 11-13 June 2019

DRUG-impurities

Foodingredients-

toxins

Detergents

Tox

UNWANTED EFFECTS

1st approach: Structure-Property Relationships

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

Gabriele CrucianiEFSA Parma, 11-13 June 2019

DRUG-impurities

Foodingredients-

toxins

Detergents

Tox

UNWANTED EFFECTS

1st approach: Structure-Property Relationships

xenobiotics

Chemical description01100011100010101

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

Gabriele CrucianiEFSA Parma, 11-13 June 2019

DRUG-impurities

Foodingredients-

toxins

Detergents

Tox

UNWANTED EFFECTS

QSPR

1st approach: Structure-Property Relationships

xenobiotics

Chemical description01100011100010101

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

Gabriele CrucianiEFSA Parma, 11-13 June 2019

1st approach: Structure-Property Relationships

Chemical description01100011100010101

Gabriele CrucianiEFSA Parma, 11-13 June 2019

1st approach: Structure-Property Relationships

Chemical description01100011100010101

Gabriele CrucianiEFSA Parma, 11-13 June 2019

1st approach: Structure-Property Relationships

Chemical description01100011100010101

Gabriele CrucianiEFSA Parma, 11-13 June 2019

1st approach: Structure-Property Relationships

Chemical description01100011100010101

Gabriele CrucianiEFSA Parma, 11-13 June 2019

DRUG-impurities

Foodingredients-

toxins

Detergents

Tox

UNWANTED EFFECTS

QSPR

1st approach: Structure-Property Relationships

AI

xenobiotics

Chemical description01100011100010101

Gabriele CrucianiEFSA Parma, 11-13 June 2019

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

Gabriele CrucianiEFSA Parma, 11-13 June 2019

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

Gabriele CrucianiEFSA Parma, 11-13 June 2019

noTox Tox

example

Gabriele CrucianiEFSA Parma, 11-13 June 2019

noTox Tox

example

Gabriele CrucianiEFSA Parma, 11-13 June 2019

o

Troglitazone

Hepatotoxic

Pioglitazone Thiazolidinediones tox pathway:

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

(14), 62-70, 2001

Gabriele CrucianiEFSA Parma, 11-13 June 2019

o

Troglitazone

Hepatotoxic

Pioglitazone Thiazolidinediones tox pathway:

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

(14), 62-70, 2001

Gabriele CrucianiEFSA Parma, 11-13 June 2019

Pioglitazone Troglitazone12 days human MIT hepatocye

Gabriele CrucianiEFSA Parma, 11-13 June 2019

PioglitazoneTroglitazone12 days human MIT hepatocyte

Gabriele CrucianiEFSA Parma, 11-13 June 2019

Tamoxifen DILI+(Steatohepatitis)

Benefit: prevent breast cancer

Risk: increased risk of uterine cancer, stroke

Risk / Benefit ??

Personalised approach

Gabriele CrucianiEFSA Parma, 11-13 June 2019

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

Gabriele CrucianiEFSA Parma, 11-13 June 2019

2 days4 days6 days8 days11

days

14 days

LipoTox Technology Platform

Gabriele CrucianiEFSA Parma, 11-13 June 2019

Tamoxifen DILI+(Steatohepatitis)

Toxicity increases

Gabriele CrucianiEFSA Parma, 11-13 June 2019

• 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?

Gabriele CrucianiEFSA Parma, 11-13 June 2019

• 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

Gabriele CrucianiEFSA Parma, 11-13 June 2019

• Challenges for studying drug combinations:

• System may include more drugs

• Suitably robust to capture combination effects

25

Drug Combinations

Gabriele CrucianiEFSA Parma, 11-13 June 2019

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

Gabriele CrucianiEFSA Parma, 11-13 June 2019

Alessandra Di Veroli

Aurora Valeri

Fabien Fontain

Laura Goracci

Massimo Baroni

Paolo Benedetti

Paolo Tiberi

Sara Tortorella

Stefano di Bona

Molecular Discovery

Thanks to …

Gabriele CrucianiEFSA Parma, 11-13 June 2019

Rosso di sera .. bel tempo si spera !!

Red sky at night, shepherd’s delight

Thanks all …