SCIENCE/TECHNOLOGY
New QSAR Techniques Eyed For Environmental Assessments Expert system, spectroscopy method use readily available data to develop quantitative structure-activity relationships for broad compound classes Stu Borman, C&EN Washington
Quantitative structure-activity relationships (QSAR) are widely used by regulatory agencies and industry to make rapid and cost-effective predictions about the toxicity and reactivity of industrial chemicals. However, some believe that use of QSAR could increase considerably in the future if limitations in some
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Many parameters are used as bases for QSAR
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Various molecular structure and property descriptors go into the formulation of quantitative structure-activity relationships (QSAR). For example, for a large number of unreactive, neutral organic chemicals, there is a strong correlation between the hydrophobicity of a compound and its lethality to fish, as measured by LC50, the chemical concentration that kills 50% of fish in a certain time. Octanol/water partition coefficient is a commonly used measure of hydrophobicity because the biophase is similar to octanol in physicochemical properties. Hydrophobicity correlates with toxicity not so much because chemicals that are more hydrophobic are more toxic, but because their rate of uptake into the biophase and rate of diffusion through cell membranes to sites of action are greater. L. S. McCarty of the biology department at the University of Waterloo, Canada, points out
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February 19, 1990 C&EN
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current QSAR techniques can be pert system and the spectroscopic overcome. For example, the data technique currently are under deneeded to set up QSAR equations velopment at the Environmental often are not readily available, and Protection Agency and in academia. QSAR correlations are frequently apQSAR techniques use molecular plicable only within narrow com- structure and physical property data pound families in which the chem- to make predictions about the bioical structures are fairly similar. logical activity (toxicity, for examThat is why some QSAR research- ple) and environmental reactivity ers are looking hopefully at new of compounds, based on data from techniques that make estimates ap- related compounds of known bioplicable to broader compound classes logical activity or reactivity. and that base predictions on readiSome say the major application ly available data sources. Such tech- of QSAR is not in environmental niques include a new expert system studies but in pharmaceutical rethat bases predictions on fundamen- search. "QSAR is used routinely in tal chemical structure theory and a almost every pharmaceutical house QSAR method that uses readily to enhance productivity and extrapavailable spectroscopic data as the olate from known data/ 7 says Peter C. basis for QSAR estimates. The ex- Jurs, professor of chemistry at Pennthat "it's not what's in the water that kills the organism but what gets inside the organism." For relatively unreactive organic chemicals, says McCarty, the lethal body burden is roughly constant—about 3 millimoles per kg for fathead minnows, for example.
Because unreactive organic chemicals lack specific toxic modes of action, their toxicity is attributed to narcosis, a term for generalized biological depression. "Narcosis is a kind of minimal effect because in principle every organic chemical, even the inert
QSAR predicts activity data from structure/property data Structure/property
descriptors
Hydrophobicity Octanol/water partition coefficients Topological descriptors Molecular connectivity index Eiectronic descriptors Hammett constants Dipole moments Molar refractivities ionization potentials Steric effects Taft constants Van der Waals radii Total surface area
Activity
Applications
Therapeutic response
Drug design
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Bioactivity Environmental fate Reactivity Transport Toxicity Narcosis
