Quantitative structure-activity limitations

There have been several, albeit limited, attempts to develop quantitative, structure-activity relationships in drug absorption (e.g., Ref. 21). Such relationships... 

Quantitative Structure-Activity Relationship studies search for a relationship between the activity/toxicity of chemicals and the numerical representation of their structure and/or features. The overall task is not easy. For instance, several environmental properties are relatively easy to model, but some toxicity endpoints are quite difficult, because the toxicity is the result of many processes, involving different mechanisms. Toxicity data are also affected by experimental errors and their availability is limited because experiments are expensive. A 3D-QSAR model reflects the characteristics of... 

C-H and N-H bond dissociation energies (BDEs) of various five- and six-membered ring aromatic compounds (including 1,2,5-oxadiazole) were calculated using composite ab initio CBS-Q, G3, and G3B3 methods. It was found that all these composite ab initio methods provided very similar BDEs, despite the fact that different geometries and different procedures in the extrapolation to complete incorporation of electron correlation and complete basis set limit were used. A good quantitive structure-activity relationship (QSAR) model for the C-H BDEs of aromatic compounds... 

REACH is an extraordinarily ambitious program. There are discussions underway regarding proposals to limit the numbers of chemicals to be subjected to these requirements. The potential for toxicological testing on a massive scale raises questions about the availability of facilities to carry out such tests, and runs counter to the objective of reducing the numbers of animals used for such purposes. The need to accomplish REACH objectives without the overuse of laboratory animals has promoted discussion and research regarding the use of alternative methods to collect the necessary data tools such as in vitro tests and quantitative structure-activity relationships (QSARs) are being promoted, and this has led to substantial research efforts to test their predictive validity. Time will tell where all of this activity leads us. 

Oprea, T. I., Waller, C. L., and Marshall, G. R. (1994). Three dimensional quantitative structure-activity relationship of human immunodeficiency virus (I) Protease inhibitors. 2. Predictive power using limited exploration of alternate binding modes../. Med. Chem. 37, 2206-2215. 

The validity of a model is always limited to a certain domain in the parameter space. For example, if a quantitative structure-activity relationships (QSAR) model is specified for nonpolar organic chemicals in the log range from 2 to 6 and has a molecular weight below 700, then an application to substances outside this range is an improper extrapolation. Note that the parameter space may be difficult to discern for example, combinations of low values for one variable and high values for another could constitute an extrapolation if such combinations had been missing in the validation or specification of the model. Exceedence of model boundaries introduces additional uncertainty at best, but can also lead to completely incorrect outcomes. 

In in vitro permeability studies conducted in static systems, the UWL adjacent to the membrane can be up to 1500-4000 j,m thick, whereas in vivo the UWL is only 30-300 j,m in the GI tract and is negligible for the BBB [71]. The experimental system is often stirred or shaken to minimize the effects of the UWL. An orbital shaker is often not effective and can be modified by adding beads to enhance the agitation. Recently, it has been clearly demonstrated that the quantitative structure activity relationship was interfered if the UWL limited... 

Macdonald, D., Breton, R., Sutcliffe, R., and Walker, J., Uses and limitations of quantitative structure-activity relationships (QS ARs) to categorize substances on the Canadian Domestic Substance List as persistent and/or bioaccumulative, and inherently toxic to non-human organisms, SAR QSAR Environ. Res., 13, 43-55, 2002. 

It should be possible to determine the hazardous properties of a substance from its molecular structure. The properties of pharmaceuticals are almost always first predicted using computational techniques such as Quantitative Structure-Activity Relationships9 (QSAR) before further product development [39]. Most industrial chemicals have been produced before these in-silico tools were available or readily accessible10. Of course, our current knowledge and understanding of science, let alone that of a risk assessor, also limits the application of such methods. 

Figure 3. Plot of the logarithm of experimentally determined rate constants (iccat, min ) against energy barriers calculated with a QM/MM method for hydroxylation of severalparahydroxybenzoate derivatives by the enzymepara-hydroxybenzoate hydroxylase (PHBH), showing a linear correlation (r=0.96) between the calculated and experimental results [49,50]. This correlation supports the proposed mechanistic scheme, and the identification of the hydroxylation step as rate-limiting within it. It also validates the QM/MM method for this application, and shows that QM/MM results can be predictive and will be useful in the development of quantitative structure-activity relationships (QSAR). (Adapted from ref. 49, with thanks to Dr. L. Ridder).

Another limitation and restriction of these models are the data reliability of the Henry s law constants. It is very important that accurate Henry s law constants shall be available for modeling an air stripper as all design parameters and costs are strongly sensitive to the Henry s law constants (22). For many common VOCs, the constants are available in books as well as the literature. For uncommon contaminants, the constants may be looked up in an extensive database by Sander (36) or predicted by using quantitative structure-activity relationship (QSAR) model for Henry s law constant (37). However, if the data are absent or data reliability is of question, pilot testing or laboratory measurement of the Henry s law constant is recommended (38). 

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