QSARs

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QSARs

• Quantitative Structure-Activity Relationships and
  their Applications

Robin Hughes
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QSARs

• What Are They?
• Why Do We Care?
• How Are They Used?
• Limitations
• Conclusions / Whats Next?

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What Are They?

• Mathematical Models
• Chemical Structure ?Biological Activity
• Hydrophobic
• Electronic
• Steric

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Why Do We Care?

• Based on Parameters
• Time
• Cost
• Predictive

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How Are They Used?

• Recent (Past 10yrs)
• Pharmaceutical, Agricultural
• Establishing Priorities
• Estimation
• Risk Assessment
• International Decision-Making

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Studies

• Correlation between Hydrophobicity of
  Short-Chain Aliphatic Alcohols and Their Ability
  to Alter Plasma Membrane Integrity McKarns et
  al. (1996)
• Classifying Class I and Class II Compounds By
  Hydrophobicity and Hydrogen Bonding Descriptors
  S. Ren (2002)
• Structure- and Property- Activity Relationship
  Models of Microbial Toxicity of Organic Chemicals
  to Activated Sludge N. Nirmalakhandan,
  E.Egemen, C. Treviso, and S. Xu (1997)

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Correlation between Hydrophobicity of Short-Chain
Aliphatic Alcohols and Their Ability to Alter
Plasma Membrane Integrity McKarns et al. (1996)

• Lactate dehydrogenase (LDH)
• Log P ( log Kow)

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Study Design

• 2 Models
• LDH50
• EC50
• Almost Identical

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Findings

• LDH50 and EC50 are positively correlated with
  Hydrophobicity
• Models are good predictors
• Predict effects of untested chemicals

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Classifying Class I and Class II Compounds By
Hydrophobicity and Hydrogen Bonding
Descriptors S. Ren (2002)

• Class I Nonpolar Narcotic
• Baseline Toxicity
• Class II Polar Narcotic
• Above Baseline Toxicity

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Study Design

• Nonlinear model
• Discriminant Analysis
• Descriptors Used
• Log Kow
• ELUMO, EHOMO
• Q, Q-

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Findings

• Applied to 190 compounds
• 8 Misclassifications
• All 5 variables significant

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Structure- and Property- Activity Relationship
Models of Microbial Toxicity of Organic Chemicals
to Activated Sludge
N. Nirmalakhandan, E.Egemen, C. Treviso, and S.
Xu (1997)

• Concern
• Industrialization ? SOCs in wastewater
• Microorganisms used in treatment
• What are threshold levels?

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Study Design

• 4 Models
• IC50
• Experimental Data 16 chemicals

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QSAR / QPAR

• Structure/Property
• Authors define analyses dealing with
  octanol-water partition coefficients and aqueous
  solubility as QPARs
• QSARs defined using solvatochromatic parameters
  (Linear Solvation Energy Relationships - LSER)
  and molecular connectivity indices (MCI)

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Models
QSAR Models

• LSER Model
• VI, Instrinsic molar volume
• p, Polarity/Polarizability
• am, Hydrogen bond donor acidity
• ßm, Basicity

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Models
QSAR Models

• MCI Model
• Structural and Atomic Information
• Express physical, chemical, and biological
  properties

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Models
QPAR Models

• Octanol-Water Partition Model
• log P
• Used calculated values for consistency

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Models
QPAR Models

• Aqueous Solubility Model
• log S correlated with other indicators
• Hypothesis toxicity may be directly correlated
  with S
• Used experimental values

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Findings

• LSER Model
• High statistical validity, but not the best
  toxicity predictor
• Log S
• No statistically significant correlation found
• Both models above acceptable FE for
• 50 of tested chemicals

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Findings

• log P and MCI Models
• reliable and convenient
• Parameters easily available
• Further testing of utility suggested

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Findings

• Predicted vs Experimental
• LC50
• All 4 models

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Findings

• Factor of error
• FEpredictive/measured
• If FElt1 1/FE was used

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Limitations

• Activity-Specific
• Experimental Error
• Too Many Parameters
• Validation
• Projecting Beyond Sample Space

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Conclusions

• Similar Parameters
• Still Secondary
• Low-Cost (both time and )
• Mechanism of Action
• Still in development

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Whats Next?

• Databases
• Predictive Capabilities
• Prevention
• Remediation?

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Works Cited

• Cronin, M. et al. (2003). Use of Quantitative
  Structure-Activity Relationships in International
  Decision-Making Frameworks to Predict Health
  Effects of Chemical Substances. In Journal of the
  National Institute of Environmental Health
  Sciences. (www.ehponline.org).
• McKarns, S., et al. (1997). Correlation between
  Hydrophobicity of Short-Chain Aliphatic Alcohols
  and Their Ability to Alter Plasma Membrane
  Integrity. In Fundamental and Applied Toxicology,
  36 62-70.
• Nirmalakhandan, N.,.Egemen, E, Treviso, C., and
  Xu, S. (1998). Structure- and Property- Activity
  Relationship Models of Microbial Toxicity of
  Organic Chemicals to Activated Sludge. IN
  Ecotoxicology and Enironmental Safety,
  39112-119.
• Rand, G.M., Ed. Fundamentals of Aquatic
  Toxicology, 2nd Ed. Taylor and Francis.
  Philadelphia, PA, 1995.
• Ren, S. (2002). Classifying Class I and Class II
  Compounds By Hydrophobicity and Hydrogen Bonding
  Descriptors . In Environmental Toxicology, 17
  415-423.

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QSAR and Modeling Society

• http//www.ndsu.nodak.edu/qsar_soc/aboutsoc/applic
  at.pdf