Quantitative structure-activity relationships hydrophobicity descriptor

Kim, K.H. (1993d) Separation of electronic, hydrophobic, and steric effects in 3D quantitative structure-activity relationships with descriptors direcdy from 3D structures using a comparative molecular field analysis (CoMFA) approach. Curr. Top. Med. Chem., 1, 453-467. 

Besides the aforementioned descriptors, grid-based methods are frequently used in the field of QSAR quantitative structure-activity relationships) [50]. A molecule is placed in a box and for an orthogonal grid of points the interaction energy values between this molecule and another small molecule, such as water, are calculated. The grid map thus obtained characterizes the molecular shape, charge distribution, and hydrophobicity. 

The octanol-water partition coefficient, Kow, is the most widely used descriptor of hydrophobicity in quantitative structure activity relationships (QSAR), which are used to describe sorption to organic matter, soil, and sediments [15], bioaccumulation [104], and toxicity [105 107J. Octanol is an amphiphilic bulk solvent with a molar volume of 0.12 dm3 mol when saturated with water. In the octanol-water system, octanol contains 2.3 mol dm 3 of water (one molecule of water per four molecules of octanol) and water is saturated with 4.5 x 10-3 mol dm 3 octanol. Octanol is more suitable than any other solvent system (for) mimicking biological membranes and organic matter properties, because it contains an aliphatic alkyl chain for pure van der Waals interactions plus the alcohol group, which can act as a hydrogen donor and acceptor. 

Quantitative structure-activity relationships represent an attempt to correlate activities with structural descriptors of compounds. These physicochemical descriptors, which include hydrophobicity, topology, electronic properties, and steric effects, are determined empirically or, more recently, by computational methods. The success of a QSAR method depends on two factors the training dataset obtained by testing a group of chemicals and the descriptors obtained from some easily measurable or calculable property of the chemicals. 

Quantitative structure-activity relationships (QSARs) are important for predicting the oxidation potential of chemicals in Fenton s reaction system. To describe reactivity and physicochemical properties of the chemicals, five different molecular descriptors were applied. The dipole moment represents the polarity of a molecule and its effect on the reaction rates HOMo and LUMO approximate the ionization potential and electron affinities, respectively and the log P coefficient correlates the hydrophobicity, which can be an important factor relative to reactivity of substrates in aqueous media. Finally, the effect of the substituents on the reaction rates could be correlated with Hammett constants by Hammett s equation. 

Quantitative structure-activity relationship (QSAR) (Hansch and Klein, 1986 Hansch and Leo, 1995) represents an attempt to correlate structural descriptors of compounds with activities. The physicochemical descriptors include numerical parameters to account for electronic properties, steric effect, topology, and hydrophobicity of analogous compounds. In its simplest form, the biochemical activities are correlated to the numerical substituent descriptors of analogous compounds tested by a linear equation such as... 

The epoch of QSAR (Quantitative Structure-Activity Relationships) studies began in 1963-1964 with two seminal approaches the a-p-7i analysis of Hansch and Fujita " and the Free-Wilson method. The former approach involves three types of descriptors related to electronic, steric and hydrophobic characteristics of substituents, whereas the latter considers the substituents themselves as descriptors. Both approaches are confined to strictly congeneric series of compounds. The Free Wilson method additionally requires all types of substituents to be suflficiently present in the training set. A combination of these two approaches has led to QSAR models involving indicator variables, which indicate the presence of some structural fragments in molecules. 

Tanaka, A. and Fujiwara, H. (1996). Quantitative Structure-Activity Relationship Study of Fibrinogen Inhibitors, ((4-(4-Amidinophenoxy)Butanoyl)Aspartyl)Valine (FK633) Derivatives, Using a Novel Hydrophobic Descriptor. J.MetLChem., 39,5017-5020. 

Tanaka, A. and Fujiwara, FI. (1996) Quantitative structure-activity relationship study of fibrinogen inhibitors ((4-(4-amidinophenoxy)butanoyl) aspartyljvaline (FK633) derivatives, using a novel hydrophobic descriptor. /. Med. Chem.,... 

Quantitative structure-activity relationships QSAR. The QSAR approach pioneered by Hansch and co-workers relates biological data of congeneric structures to physical properties such as hydrophobicity, electronic, and steric effects using linear regression techniques to estimate the relative importance of each of those effects contributing to the biological effect. The molecular descriptors used can be 1-D or 3-D (3D-QSAR). A statistically sound QSAR regression equation can be used for lead optimization. 

The octanol/water partition coefficient is one of the most frequently used descriptors in biological quantitative structure activity relationships. It is considered to reflect the hydrophobicity of a molecule and therefore to be relevant both for correlating the transport properties and the receptor binding of biologically active molecules. Since pharmacological and toxicological research often concerns poorly characterized or not yet synthesized molecules, there is a... 

Non-linear models may be fitted to data sets by the inclusion of functions of physicochemical parameters in a linear regression model—for example, an equation in n and as shown in Fig. 6.5—or by the use of non-linear fitting methods. The latter topic is outside the scope of this book but is well covered in many statistical texts (e.g. Draper and Smith 1981). Construction of linear regression models containing non-linear terms is most often prompted when the data is clearly not well fitted by a linear model, e.g. Fig. 6.4e, but where regularity in the data suggests that some other model will fit. A very common example in the field of quantitative structure-activity relationship (QSAR) involves non-linear relationships with hydrophobic descriptors such as log P or n. Non-linear dependency of biological properties on these parameters became apparent early in the... 

The solvent accessible surface area (SASA) is often used as a descriptor in quantitative structure-activity relationships (Connolly 1996). For a wide variety of molecules there is an approximate linear relation between solvation free energies and SASA. However, theoretical considerations indicate that the SASA model is incapable of accurately describing non-polar solvation phenomena at length-scales comparable to the size of a water molecule. It is more useful at large length-scales when more extended hydrophobic surfaces are in contact with the solvent. 

Stanton, D.T., Mattioni, B.E., Knittel, J.J. and Jurs, P.C. (2004) Development and use of hydrophobic surface area (HSA) descriptors for computer-assisted quantitative structure-activity and structure-property relationship studies. Journal of Chemical Information and Computer Sciences, 44, 1010-1023. 

Chemical reactivity and biological activity can be related to molecular structure and physicochemical properties. QSAR models can be established among hydrophobic-lipophilic, electronic, and steric properties, between quantum-mechanics-related parameters and toxicity and between environmental fate parameters such as sorption and tendency for bioaccumulation. The main objective of a QSAR study is to develop quantitative relationships between given properties of a set of chemicals and their molecular descriptors. To develop a valid QSAR model, the following steps are essential ... 

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