(Q)SAR

Structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR) models - collectively referred to as (Q)SARs - are theoretical models that can be used to quantitatively or qualitatively predict the physicochemical, biological (e.g. an (eco)toxicological endpoint) and environmental fate properties of compounds from the knowledge of their chemical structure.

(Q)SAR methods find application in a variety of sectors (pharma, industry, food, agro, cosmetics) for both R&D and regulatory purposes with the aim to minimize monetary, timing and ethical costs of experimental testing.

R&D applications:

  • Optimise experimental design
  • Screening and prioritisation

Regulatory applications:

  • Support priority setting procedures
  • Support experimental data (in vitro, in vivo) in weight-of-evidence assessment
  • Substitute experimental data (in vitro, in vivo)

Workflow (Q)SAR services

Endpoints

TOXICOLOGY

  • Skin irritation/corrosion
  • Eye irritation/corrosion
  • Skin senstisation (LLNA)
  • Mutagenicity
    • in vitro bacterial mutagenicity (Ames test)
    • in vitro mammalian cell mutagenicity (CHO/CHL, mouse lymphoma)
    • in vivo mammalian mutagenicity (rodents)
  • Clastogenicity
    • in vitro chromosome aberration
    • in vivo chromosome aberration
    • in vivo micronucleus
  • Acute toxicity
    • oral (mouse, rat)
  • Carcinogenicity
  • Reproductive and developmental toxicity
    • Reproductive toxicity (mouse, rat)
    • Fetal growth retard (rabbit, rat)
    • Fetal growth weight decrease (rabbit, rat)
    • Fetal death (rabbit, rat)
    • Post implantation loss (rabbit, rat)
    • Pre implantation loss (rabbit, rat)
    • Structural Dysmorphogenesis (rabbit, rat)
  • Target organ toxicity
    • Cardiotoxicity
    • Hepatotoxicity
    • Nephrotoxicity
    • Neurotoxicity
  • Endocrine disruption
    • Estrogen Receptor relative binding

ECOTOXICOLOGY

  • Aquatic toxicity
    • Acute toxicity (algae, invertebrates, fish)
    • Chronic toxicity (algae, invertebrates, fish)
  • Terrestrial toxicity
    • Short-term toxicity to Invertebrates (Honey Bee)

ENVIRONMENTAL PROPERTIES

  • Ready biodegradability
  • Abiotic Degradation
    • Hydrolysis as a function of pH
    • Photodegradation
  • Persistence (sediment, soil, water)
  • Absorption/desorption screening (Koc)
  • Bioaccumulation in aquatic species
    • Bioconcentration factor in fish (BCF)
    • Biotransformation rate in fish (kM)
    • Bioaccumulation factor in fish (BAF)

PHYSICHO-CHEMICAL PROPERTIES

  • Melting point
  • Boiling point
  • Vapour pressure
  • Water solubility
  • Partition coefficient n-octanol/water (LogKow or LogP)
  • Dissociation constant (pKa)
  • Distribution coefficient n-octanol/water (LogD)

PHARMACOKINETICS / ADME

  • Passive Absorption (%HIA - human intestinal absorption)
  • Oral Bioavailability (%F - fraction bioavailable)
  • Distribution
    • plasma protein binding (PPB%)
    • volume of distribution (Vd)
  • Excretion
    • Total body clearance (ke, min-1)
  • Metabolism
    • P450 Inhibition (CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C19)
    • P450 Substrate specificity (CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C19)
    • Regioselectivity of Metabolism
  • Blood Brain Barrier Permeation
    • BBB permeation rate (LogPS)
    • brain/plasma distribution ratio (LogBB)
    • CNS activity
  • P-gp Specificity (inhibition and substrate specificity)

For each endpoint, we employ a battery of predictive models implemented in commercial software (Leadscope, ACD/Percepta, ChemTunes) as well as freeware (VEGA, Toxtree, EPI Suite, ECOSAR and OECD QSAR Toolbox)

  • Valid (Q)SAR models following the OECD validation principles
  • Defined applicability domains and/or measures for reliability assessment of predictions
  • Visualization of analogue compounds from the training set with experimental data

Documentation

(Q)SAR predictions are documented in a detailed report structured in accordance with regulatory requirements (ECHA, OECD).

Reporting types:

  • STANDARD Reporting
    • Report compiled according to ECHA guideline
  • QMRF/QPRF Reporting
    • Report compiled according to ECHA guideline
    • QSAR Model Reporting Format (QMRF)
    • QSAR Prediction Reporting Format (QPRF)
  • IUCLID Reporting
    • Report compiled according to ECHA guideline
    • QSAR Model Reporting Format (QMRF)
    • QSAR Prediction Reporting Format (QPRF)
    • IUCLID study record