Quantitative structure-solubility relationship

Two approaches to quantify/fQ, i.e., to establish a quantitative relationship between the structural features of a compoimd and its properties, are described in this section quantitative structure-property relationships (QSPR) and linear free energy relationships (LFER) cf. Section 3.4.2.2). The LFER approach is important for historical reasons because it contributed the first attempt to predict the property of a compound from an analysis of its structure. LFERs can be established only for congeneric series of compounds, i.e., sets of compounds that share the same skeleton and only have variations in the substituents attached to this skeleton. As examples of a QSPR approach, currently available methods for the prediction of the octanol/water partition coefficient, log P, and of aqueous solubility, log S, of organic compoimds are described in Section 10.1.4 and Section 10.15, respectively. 

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]. 

Liu, R., So, S.-S. Development of quantitative structure-property relationship models for early ADME evaluation in drug discovery. 1. Aqueous solubility./. Chem. Inf. Comp. Set. 2001, 41, 1633-1639. 

Raevsky, O. A., Schaper, K.-J. Physicochemical descriptors governing the solubility and partitioning of chemicals in water-solvent-gas systems. In Abstracts of 12th International Workshop on Quantitative Structure-Activity Relationships in Environmental Toxicology, Lyon, France, 2006, p. 23. 

S. Prediction of aqueous solubility of organic compounds using a quantitative structure-property relationship. J. Pharm. Sd. 2002, 91,1838-1852. 

Bocek K. 1976. Relationships among activity coefficients, partition coefficients and solubilities. In Tichy M, ed. Quantitative structure-activity relationships. Basel and Stuttgart Birkhauser Verlag, 231-240. 

There is a continuing effort to extend the long-established concept of quantitative-structure-activity-relationships (QSARs) to quantitative-structure-property relationships (QSPRs) to compute all relevant environmental physical-chemical properties (such as aqueous solubility, vapor pressure, octanol-water partition coefficient, Henry s law constant, bioconcentration factor (BCF), sorption coefficient and environmental reaction rate constants from molecular structure). 

Dunnivant, F. M., Elzerman, A. W., Jurs, P. C., Hansen, M. N. (1992) Quantitative structure-property relationships for aqueous solubilities and Henry s law constants of polychlorinated biphenyls. Environ. Sci. Technol. 26, 1567-1573. 

Pollutants with high VP tend to concentrate more in the vapor phase as compared to soil or water. Therefore, VP is a key physicochemical property essential for the assessment of chemical distribution in the environment. This property is also used in the design of various chemical engineering processes [49]. Additionally, VP can be used for the estimation of other important physicochemical properties. For example, one can calculate Henry s law constant, soil sorption coefficient, and partition coefficient from VP and aqueous solubility. We were therefore interested to model this important physicochemical property using quantitative structure-property relationships (QSPRs) based on calculated molecular descriptors [27]. 

Octanol/water partition coefficients, Pow, which measure the relative solubilities of solutes in octanol and in water, are widely used as descriptors in quantitative structure-activity relationships (QSAR), for example in pharmacological and toxicological applications.49 Since experimental values of these are not always available, a number of procedures for predicting them have been proposed (see references in Brinck et al.).50... 

Huanxiang L, Xiaojun Y, Ruisheng Zh, Mancang L, Zhide H, Botao F (2005) Accurate quantitative structure-property relationship model to predict the solubility of C60 in various solvents based on a novel approach using a least-squares support vector machine. J. Phys. Chem. Sect B. 109 20565-20571. 

A quantitative analysis of the structure-retention relationship can be derived by using the relative solubility of solutes in water. One parameter is the partition coefficient, log P, of the analyte measured as the octanol-water partition distribution. In early work, reversed-phase liquid chromatography was used to measure log P values for drug design. Log P values were later used to predict the retention times in reversed-phase liquid chromatography.The calculation of the molecular properties can be performed with the aid of computational chemical calculations. In this chapter, examples of these quantitative structure-retention relationships are described. 

Dunnivant, F.M. and Elzerman, A.W. Aqueous solubility and Henry s law constant for PCB congeners for evaluation of quantitative structure-property relationships (QSPRs), Chemosphere, 17(3) 525-531, 1988. 

Yaeee, D., Cohen, Y., Espinosa, G., Arenas, A., and Giealt, E. A fuzzy ARTMAP based on quantitative structure-property relationships (QSPRs) for predicting aqueous solubility of organic compounds. 

There are several properties of a chemical that are related to exposure potential or overall reactivity for which structure-based predictive models are available. The relevant properties discussed here are bioaccumulation, oral, dermal, and inhalation bioavailability and reactivity. These prediction methods are based on a combination of in vitro assays and quantitative structure-activity relationships (QSARs) [3]. QSARs are simple, usually linear, mathematical models that use chemical structure descriptors to predict first-order physicochemical properties, such as water solubility. Other, similar models can then be constructed that use the first-order physicochemical properties to predict more complex properties, including those of interest here. Chemical descriptors are properties that can be calculated directly from a chemical structure graph and can include abstract quantities, such as connectivity indices, or more intuitive properties, such as dipole moment or total surface area. QSAR models are parameterized using training data from sets of chemicals for which both structure and chemical properties are known, and are validated against other (independent) sets of chemicals. 

QSAR Methods for Fluid Solubility Prediction, Several group contribution methods for predicting liquid solubilities have been developed. These methods as well as other similar methods are often called quantitative structure-activity relationships (QSARs). This field is experiencing rapid development. 

Puri, S., J. S. Chickos, and W. J. Welsh. 2003. Three-dimensional quantitative structure-property relationship (3D-QSPR) models for prediction of thermodynamic properties of polychlorinated biphenyls (PCBs) Enthalpies of fusion and their application to estimates of enthalpies of sublimation and aqueous solubilities.J. Chem. Inf. Comput. Sd3 55-62. 

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