Quantitative Structure-Activity Relations QSAR

Toxicity is measured by the concentration in mg liter-1 of a compound that causes the death of a certain percentage (usually 50 or 100%) of the test population of a chosen organism (e.g., silvery minnows) in a chosen time (e.g., 96 hours). For organic inhibitors, the higher the concentration needed to achieve a lethal dose of 50%, the less toxic the inhibitor. In Table 12.3 the actual lethal concentration (LC50) (at 96 hr) is compared with that calculated by means of a quantitative structure-activity relation (QSAR). The basic calculation is that of the distribution coefficient of the inhibition of the primary alcohol octanol. 

Other Examples of the Use of Principal Properties Characterization by principal properties has been reported for classes of compounds in applications other than organic synthesis Aminoacids, where principal properties have been used for quantitative structure-activity relations (QSAR) of peptides [64], Environmentally hazardous chemicals, for toxicity studies on homogeneous subgroups [65]. Eluents for chromatography, where principal properties of solvent mixtures have been used for optimization of chromatographic separations in HPLC and TLC [66],... 

Aminoacids, where principal properties have been used to establish quantitative structure-activity relations (QSAR) for peptides.[29] In this context, a more elaborate concept, dedicated principal properties[ iO] has been suggested where the modelling process is carried out in several steps to achieve maximum predictability of the QSAR models. We do not go into details on this. 

This section reviews MM/MD theoretical work, which addresses the entrance of the substrate to the pocket, its binding, and the exit of the substrate. Much theoretical work that rely on quantitative structure activity relations, QSAR, is not reviewed, but can be found in the authoritative treatment of Lewis . ... 

A gas phase is converted to a liquid phase when appropriate pressure and temperature are present (which means that molecules become so close that a new phase, liquid, is formed). If temperature is lowered even further, then a solid phase is formed. Liquid water freezes at 0°C to form solid ice (at 1 atm). This kind of transition can be explained by analyzing molecular interactions in liquids, which are responsible for their physicochemical properties (such as boiling point, melting point, heat of vaporization, and surface tension). Since molecular structure is the basic parameter involved in these transitions, one needs to analyze the former characteristics. This analysis is the basis of the quantitative structure activity related (QSAR) (Barnes, 2011 Birdi, 2003b). QSARs have been used to predict physical properties of liquids in extensive detail (Birdi, 2003a Gotch, 1974 Livingstone, 1996). 

Quantitative Structure—Activity Relationships (QSAR). Quantitative Stmcture—Activity Relationships (QSAR) is the name given to a broad spectmm of modeling methods which attempt to relate the biological activities of molecules to specific stmctural features, and do so in a quantitative manner (see Enzyme INHIBITORS). The method has been extensively appHed. The concepts involved in QSAR studies and a brief overview of the methodology and appHcations are given here. 

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]. 

Thiadiazole 1 and its derivatives were used as model compounds for the calculation of molecular parameters related to physical properties for their use in quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) studies <1999EJM41, 2003IJB2583, 2005JMT27>. 

Classical chemo metric methods, such as the Quantitative Structure Activity Relationships, QSAR, can be used to relate the chemical characteristics of a molecule to its structure. QSAR methods have been widely used in the pharmaceutical field for drug design, but they are also very useful for many other... 

To aid in assessing the risks associated with large numbers of environmental contaminants, quantitative-structure-activity relationships (QSARs) have been developed covering nearly all biological effects or other endpoints in both aquatic and terrestrial species (Connell, 1990). QSARs relate chemical structural... 

QSAR = quantitative structure activity relations, cf e.g. Jastorff, Stormann, Wolcke 2003... 

The underlying theory of Quantitative Structure-Activity Relationship (QSAR) is that biological activity is directly related to molecular structure. Therefore, molecules with similar structure will possess similar bioactivities for similar proteins/receptors/enzymes and the changes in structure will be represented through the changes in the bioactivities. The best general description of a QSAR model is... 

Lewis, D. F. V., Wiseman, A., and Tarbit, M. H. (1999) Molecular modeling of lanosterol 14-alpha-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivatives../. Enz. Inhib. 14, 175-192. 

Moon, T., Chi, M. H., Kim, D.-H., Yoon, C. N., and Choi, Y.-S. (2000) Quantitative structure-activity relationships (QSAR) study of flavonoid derivatives for inhibition of cytochrome P450 1A2. Quant. Struct.-Act. Relat. 19, 257-263. 

It is important to consider the molecular interactions in liquids that are responsible for their physicochemical properties (such as boiling point, melting point, heat of vaporization, surface tension, etc.), which enables one to both describe and relate the different properties of matter in a more clear manner (both qualitatively and quantitatively). These ideas form the basis for quantitative structure activity relationship (QSAR Birdi, 2002). This approach toward analysis and application is becoming more common due to the enormous help available from computers. 

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. 

Tang, W.Z. and Pierotti, A.J., WWW database of disinfection by-product properties and related QSAR information, in Handbook on Quantitative Structure Activity Relationships (QSARs) for Pollution Prevention, Toxicity Screening, Risk Assessment and Web Applications, Walker, J.D., Ed, SETAC Press, Pensacola, FL, 2000. 

Methods to predict the hydrolysis rates of organic compounds for use in the environmental assessment of pollutants have not advanced significantly since the first edition of the Lyman Handbook (Lyman et al., 1982). Two approaches have been used extensively to obtain estimates of hydrolytic rate constants for use in environmental systems. The first and potentially more precise method is to apply quantitative structure/activity relationships (QSARs). To develop such predictive methods, one needs a set of rate constants for a series of compounds that have systematic variations in structure and a database of molecular descriptors related to the substituents on the reactant molecule. The second and more widely used method is to compare the target compound with an analogous compound or compounds containing similar functional groups and structure, to obtain a less quantitative estimate of the rate constant. 

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