Potency quantitative structure-activity

Spsted, H. et al., Ranking of hair dye substances according to predicted sensitization potency quantitative structure-activity relationships, Contact Dermatitis, 51, 241, 2004. 

We have developed a quantitative structure-activity model for the variations in potency among the nitrosamines and, more recently, a related model for the variation in target organ for a smaller set of nitrosamines. We are currently developing a model for interspecies variation in susceptibility toward carcinogenic nitrosamines. The model for organ selectivity requires terms for the parent nitrosamine as well as for the hypothesized metabolites while the model for potency variations contains terms only for the unmetabolized parent compound. 

There appears now to be ample evidence that the variations in carcinogenicity among the nitrosamines are systematically and rationally related to structure and that several Indices of carcinogenic potency can be used as indices of biological response for the generation of quantitative structure-activity models (11-17). 

Hermens, J., Canton, H., Janssen, P., and de Jong, R. Quantitative structure-activity relationships and toxicity studies of mixtures of chemicals with an anaesthetic potency acute lethal and sublethal toxicity to Daphnia magna, Aquat. Toxicol, 5(2) 143-154, 1984. 

Drug binding is enhanced by hydrophobicity in that portion of the drug that binds to the pocket toe. Quantitative structure-activity relationship (QSAR) analysis of these compounds have consistently shown that the most predictive parameter of antiviral activity is a measure of hydrophobicity, the octanol water partition coefficient (logP) [80,82,85]. These studies have also consistently shown that there is no apparent correlation between electrostatic potential or dipole moment and potency. 

Hellberg, S., Sjostrom. M. and Wold. S. The Prediction of Bradykinin Potentiating Potency of Pentapeptides. An Example of a Peptide Quantitative Structure-Activity Relationship. Acta Chem. Scand. 1986, B40, 135-140. 

Hocart, S.J., Reddy, V., Murphy, W.A. and Coy, D.H. (1995). Three-Dimensional Quantitative Structure-Activity Relationships of Somatostatin Analogs. 1. Comparative Molecular Field Analysis of Growth Hormone Release Inhibiting Potencies. J.Med.Chem., 38,1974-1989. 

In keeping with this method, several approaches have been developed to document methods and dose-response relationships for irritation in humans. This work suggests that, at least for nonreactive compounds such esters, aldehydes, ketones, alcohols, carboxylic acids, aromatic hydrocarbons, and pyridine, the percentage of vapor pressure saturation of a compound is a reasonable predictor of its irritant potency. Specific physical properties of molecules predict overall irritation potential. This work is based on the identification of irritant thresholds for homologous series of specific agents. Quantitative structure-activity relationships derived from such work suggests a reasonable model to explain mucosal irritation. 

In studies of quantitative structure activity relationships (QSAR), the relative potencies of a series of drugs are subjected to analysis with the hope that biological potency will be described by a mathematical equation. QSAR is an actuarial or statistical method in which only objective data are used with no intrusion of models or mechanistic hypotheses. The equation that is obtained not only accounts for the relative potencies of the compounds, but from it are deduced predictions of the potencies of untested compounds if the equation is valid, the predictions are ineluctable. The method thus has the capacity of yielding new (structurally related) drugs with desired potency, perhaps drugs with enhanced selectivity or fewer side effects. 

Classical Quantitative Structure-Activity Relationship Techniques The early QSAR models for calcium channel ligands were based on classical Hansch analysis and elucidated the structural requirements for the binding of molecules to their receptors [111-115], It was found that various steric (Bl, L), electronic (a), and hydrophobic (n) parameters or their combination correlated well with the potency of various DHPs [111]. QSAR analysis of another set of DHPs revealed good correlations between electronic properties (F-constants) of the phenyl ring substituents and binding affinities or functional potency [112] lipophilicity as well as ortho- and meta-substituents inductivity... 

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