Quantitative Structure-Activity Correlations

The availability of formation constants for a large number of structurally diverse alkylammonium ions also encourages attempts to identify quantitatively those chemical features of a resident ligand species that are responsible for stability and selectivity within complexes of cucurbituril. In order to secure interpretable results, a subset of data was compiled, restricted to mono-substituted ammonium ions carrying exclusively alkyl or thioether residues [9]. Only included were moieties for which internal complexation with cucurbituril was established (NMR evidence) and for which substrate-specific overcrowding (such as with the arenes) was unlikely. A short list consisting of the first 24 guests in Table 1 was 

Initial attempts to correlate the affinity of ligands toward cucurbituril using independently estimable parameters such as van der Waals molecular surface area or molecular volume of the guests were relatively unsua sful. The difficulty apparently is that the interior of the receptor has a definite shape and distribution of polarity, so that complementarity between cucurbituril and its ligand depends more subtly upon structure of the bound entity. Consequently we opted for an empirical treatment of our data, which would yield an indication of how particular regions of the interior of cucurbituril interact with ligands. 

In order to process the emended data in as unprejudiced a manner as possible, we adopted as our fundamental variable for correlating structure with affinity the intramolecular distance of an alkyl fragment of a bound ligand from its ammonium ion. The rationale for this approach is that the binding site for the 

In principle, a thermodynamic value for the ion-dipole interaction could be acquired as well by the incorporation of several alkanediamines into our data set in the foregoing analysis. However, a second ammonium ion has in fact a disproportionate effect, and it cannot be meaningfully placed on the same scale 

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We chose 60 compounds with pl50 values ranging from 7.1 to 4.9 and subjected them to regression analysis using several physicochemical parameters (Table I). The 60 compounds contained variations in six positions of the basic structure. Quantitative structure-activity correlations with as many individual uncouplers in one equation have not yet been published. As far as we know, the Hansch approach has been applied to uncouplers of oxidative phosphorylation only twice first in 1965 by Hansch and co-workers to phenols and recently by Muraoka and Terada to N-phenylanthranilic acids. From Muraoka s data we recalculated the correlation with w and o- and obtained an equation which gave the best fit (last equation, Figure 3). 

These considerations show that quantitative structure-activity correlations with uncouplers can be used as a predictive tool (18) not only for... 

Fujita, T. (1981). The Ortho Effect in Quantitative Structure-Activity Correlations. AnalChim. Acta, 133,667-676. 

Schaad, L.J. and Hess Jr., B.A. (1977). Theory of Linear Equations as Applied to Quantitative Structure-Activity Correlations. J.Med.Chem.,20, 619-625. 

Simon, Z. and Szabadai, Z. (1973). Minimal Steric Difference-Parameter and the Importance of Steric Fit for Quantitative Structure-Activity Correlations. Studia Biophys, 39,123-132. 

Lien, E. J., Rodrigues de Miranda, J. E, Ariens, E. J. Quantitative structure-activity correlation of optical isomers a molecular basis for Pfeiffer s rule. Mol. Pharmacol. 1976, 12, 598-604. 

In order to establish quantitative structure-activity correlates, the Hansch analysis of compounds represented by structures 12 and 13, was carried out. This resulted in a structure-activity correlation given by the equation below [7],... 

Bagchi, M.C., Maiti, B.C., Mills, D. and Basak, S.G. (2004b) Usefulness of graphical invariants in quantitative structure-activity correlations of tuberculostatic drugs of the isonicotinic add hydrazide type./. Mol. Model, 10, 102-111. 

Further major contributions to, development of, and applications of quantitative structure-activity correlations began in 1956 with the work of Bruice and co-workers (29). Their empirical, mathematical method was applied to the correlation of thyroxine-like activities of a series of congeners with the sum of constants assigned to different substituents of the molecules. Using Equation 4 they obtained excellent correlations... 

At the time that the basic formulation and testing of the mathematical models of quantitative structure-activity correlations were being made, another type of approach, the linear free-energy related model, was introduced (2). Using the basic Hammett equation (22, 36) for the chemical reactions of benzoic acid derivatives (Equation 12), several investigators attempted quantitative correlations between physicochemical properties... 

Whittaker performed quantitative structure-activity correlation studies and showed that within a series of m-substituted alcohols the rates correlate with Om- Thus the greater reactivity of m-methoxybenzyl alcohol relative to chloro- and nitro-benzyl alcohol is consistent with the electronic properties of the benzylic bond. This would correspond to hydrogen atom transfer as a key mechanistic step (see below). 

Furthermore the odorivectors could be treated the same way, with the same methods, as drug molecules are in QSAR (Quantitative Structure Activity Correlation). A computerized approach to biochemical quantitative structure-activity-correlations was introduced by the HANSCH APPROACH (ll). Definition of all the essential profiles, those capable of being expressed in monoosmatic components, would afford the foundation on which an algorithm for the calculation of odor quality based on the chemical structure of the odorivector conceivably could be designed. 

Fujita, T. 1981. The ortho effect in quantitative structure-activity correlations. Analytical Chim. Acta 133 667-676. 

Acute toxicity in fish, bioconcentration in fish, chlorinated hydrocarbons, chlorinated phenols, molecular connectivity indices, molecular topology, nonempirical quantitative modelling of environmental properties, polycyclic aromatic hydrocarbons, quantitative structure activity correlations, soil sorption, Pimephales promelas, fathead minnow, connectivity indices, sheepshead minnows, Cyprinodon variegatus. 

PW91 (Perdew, Wang 1991) a gradient corrected DFT method QCI (quadratic conhguration interaction) a correlated ah initio method QMC (quantum Monte Carlo) an explicitly correlated ah initio method QM/MM a technique in which orbital-based calculations and molecular mechanics calculations are combined into one calculation QSAR (quantitative structure-activity relationship) a technique for computing chemical properties, particularly as applied to biological activity QSPR (quantitative structure-property relationship) a technique for computing chemical properties... 

Quantitative Structure—Activity Relationships. Many quantitative stmcture—activity relationship (QSAR) studies of progestins have appeared in the Hterature and an extensive review of this work is available (174). QSAR studies attempt to correlate electronic, steric, and/or hydrophobic properties to progestational activity or receptor binding affinity. A review focusing on the problems associated with QSAR of steroids has been pubUshed (175). 

In 1868 two Scottish scientists, Crum Brown and Fraser [4] recognized that a relation exists between the physiological action of a substance and its chemical composition and constitution. That recognition was in effect the birth of the science that has come to be known as quantitative structure-activity relationship (QSAR) studies a QSAR is a mathematical equation that relates a biological or other property to structural and/or physicochemical properties of a series of (usually) related compounds. Shortly afterwards, Richardson [5] showed that the narcotic effect of primary aliphatic alcohols varied with their molecular weight, and in 1893 Richet [6] observed that the toxicities of a variety of simple polar chemicals such as alcohols, ethers, and ketones were inversely correlated with their aqueous solubilities. Probably the best known of the very early work in the field was that of Overton [7] and Meyer [8], who found that the narcotic effect of simple chemicals increased with their oil-water partition coefficient and postulated that this reflected the partitioning of a chemical between the aqueous exobiophase and a lipophilic receptor. This, as it turned out, was most prescient, for about 70% of published QSARs contain a term relating to partition coefficient [9]. 

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... 

Govers, H., Ruepert, C., Aiking, H. (1984) Quantitative structure-activity relationships for polycyclic aromatic hydrocarbons Correlation between molecular connectivity, physico-chemical properties, bioconcentration and toxicity in Daphnia pulex. Chemosphere 13, 227-236. 

The overall importance of the medium on the reaction rates has been shown previously, but the nature and extent of solute-solvent interactions can alter tremendously various properties of the nucleophile the variations are usually satisfactorily correlated by some of the several quantitative structure-activity relationships (QSAR) that have been discussed37,38,51,96. The term quantitative structure-property relationship (QSPR) has been recently proposed for cases where a specific property, such as the basicity, is examined97. 

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