Quantitative Shape-Activity Relations

QUANTITATIVE SHAPE - ACTIVITY RELATIONS) IN DRUG DESIGN AND MOLECULAR ENGINEERING... 

The QShAR (Quantitative Shape-Activity Relations) method, combined with the integrated main and side effect modeling of bioactive molecules, forms the conceptual basis of the approaches described in this chapter. The density scalable FSGH method for a simple representation of molecular bodies, in combination with the Shape Group Method and various other shape code approaches for quantitative shape analysis, as well as the multiple shape ranking methods for integrated main and side effect analysis, are the components of a computational implementation of the basic concepts. 

Mezey, P.G. (1992). Shape-Similarity Measures for Molecular Bodies A Three-Dimensional Topological Approach to Quantitative Shape-Activity Relations. J.Chem.lnf.Comput.Sci., 32, 650-656. 

Mezey PG (1999) Quantitative Shape — Activity Relations (QShAR), Molecular Shape Analysis, Charge Cloud Holography, and Computational Microscopy. In Walker JD (ed) QSARs in Environmental Toxicology — VIII. QSARs for Predicting Endocrine Disruption, Chemical Persistence and Effects. SETAC Publ (in press)... 

One application of the shape group method is the study of quantitative shape activity relations, QShAR, employed in drug design and in toxicology. ... 

In the practice of potentiometric titration there are two aspects to be dealt with first the shape of the titration curve, i.e., its qualitative aspect, and second the titration end-point, i.e., its quantitative aspect. In relation to these aspects, an answer should also be given to the questions of analogy and/or mutual differences between the potentiometric curves of the acid-base, precipitation, complex-formation and redox reactions during titration. Excellent guidance is given by the Nernst equation, while the acid-base titration may serve as a basic model. Further, for convenience we start from the following fairly approximate assumptions (1) as titrations usually take place in dilute (0.1 M) solutions we use ion concentrations in the Nernst equation, etc., instead of ion activities and (2) during titration the volume of the reaction solution is considered to remain constant. 

Quantitative structure-activity relationships are primarily used for drug design. The underlying principle is that the shape and noncovalent interactions are the main contributors to the selectivity of the binding of substrates to an active center. Therefore, it must be possible to correlate structural properties of substrates with their activity. The assumptions on which QSAR methods are generally based are that all substrates bind to the same site, that structurally related compounds bind with a similar orientation and that dynamic effects can be ignored. 

One could think about measuring b directly in a separate adsorption experiment. However, it has been found that the adsorption thus measured has no quantitative relation to the adsorption leading to a catalytic reaction. Not only the amounts adsorbed, but even the shape of the isotherm and the sensitivity to poisoning or surface alterations are totally different. The reason is that the adsorption experiment measures the total surface under favorable conditions (B.E.T. method), whereas the catalysis takes place on a quantitatively entirely different active ... 

The classical (or semiclassical) equation for the rate constant of e.t. in the Marcus-Hush theory is fundamentally an Arrhenius-Eyring transition state equation, which leads to two quite different temperature effects. The preexponential factor implies only the usual square-root dependence related to the activation entropy so that the major temperature effect resides in the exponential term. The quadratic relationship of the activation energy and the reaction free energy then leads to the prediction that the influence of the temperature on the rate constant should go through a minimum when AG is zero, and then should increase as AG° becomes either more negative, or more positive (Fig. 12). In a quantitative formulation, the derivative dk/dT is expected to follow a bell-shaped function [83]. 

Fumed silica acts as a highly reinforcing filler in silicone elastomers. Its activity results fi-om its highly dispersed particle structure, high surface area and surface energy. To better understand the interplay of these properties first studies on gas adsorption of hexamethylsiloxane on hydrophilic and silylated silica have been conducted. The shape of the adsorption isotherm revels the existence of low- and high-energy adsorption sites, the latter qualitatively seem to be related to reinforcement of the silicone elastomer. Further quantitative studies in this field are needed. 

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