(Quantitative) Structure-Activity Relationships

(Q)SAR

Why QSAR

• Safety evaluation

• Alternative testing methods

• High throughput, efficiency

• Predictive value

What is QSAR

• In silico toxicity testing

• “Machine learning” method

• Pattern recognition

Applications

• Drug discovery - mechanism based design

• Drug development - efficacy/toxicity

• Environmental toxicity - human and wildlife

• Environmental fate - accumulation, biodegradation, photodegradation, etc

Categories of chemicals

• Drugs: agonists, antagonists, inhibitors of specific molecules

• POPs• Endocrine disruptors• Carcinogens• Narcotics in aquatic environment• Pesticides• Neurotoxins

Mutagenicity

Other in vitro tests

Mutagenicity in vivo

Carcinogenicity

FDA Cancer Male Rat CommercialCDER Proprietary MRFDA Cancer Female RatCDER Proprietary FRFDA Cancer Male MouseCDER Proprietary MMFDA Cancer Female MouseCDER Proprietary FM

CPDB Rat TD50 mg/kg DK-EPACPDB Mouse TD50 mg/kgCPDB Liver Specific (Rat or Mouse)

To open the database, visit http://ecbqsar.jrc.it

Tamura 2003 OP pesticides and androgen receptor

Structure analogues of non-steroidal antiandrogens

Testosterone antagonism by methylparathion and ethylfenitrothion

Structure alignment of DHT and fenitrothion in receptor binding site

Androgen receptor conformation and

critical residues for ligand interaction