D-QSAR Methods

A widely used 3-D QSAR method that makes use of PLS is comparative molecular field analysis (CoMFA), in which a probe atom is used to calculate the steric and electronic fields at numerous points in a 3D lattice within which the molecules have been aligned. Poso et al. [56] used the technique to model the binding of coumarins to cytochrome P450 2A5, with similar results to those obtained by Bravi and Wikel [55]. Shi et al. [57] used it to model the estrogen receptor binding of a large diverse set of compounds, and Cavalli et al. [58] used it to develop a pharmacophore for hERG potassium... 

Sippl W. Binding affinity prediction of novel estrogen receptor ligands using receptor-based 3-D QSAR methods. Bioorg Med Chem 2002 10 3741-55. 

Recent developments include three-dimensional (3-D) QSAR methods which relate regions of the binding site with complementary properties [85]. The conformation of each molecule then needs be computed and the descriptor property determined. Another interesting development is the electron topological (ET) approach in QSAR methods [86]. Molecular compounds are described by quadratic matrices (n, n number of atoms), where elements close to the diagonal represent electronic parameters while the other elements are related to the structure. 

Basak, S. C., Natarajan, R., Mills, D. Structure-activity relationships for mosquito repellent aminoamides using the hierarchical QSAR method based on calculated molecular descriptors, 2005, pp. 958-963. 

Sivakumar, P.M., Babu, S.K.G., Mukesh, D. QSAR studies on chalcones and flavonoids as antituberculosis agents using genetic function approximation (GFA) method. Chem. Pharm. Bull. 2007, 55, 44-9. 

Any QSAR method can be generally defined as an application of mathematical and statistical methods to the problem of finding empirical relationships (QSAR models) of the form ,- = k(D, D2,..., D ), where ,- are biological activities (or other properties of interest) of molecules, D, P>2,- ,Dn are calculated (or, sometimes, experimentally measured) structural properties (molecular descriptors) of compounds, and k is some empirically established mathematical transformation that should be applied to descriptors to calculate the property values for all molecules (Fig. 6.1). The goal of QSAR modeling is to establish a trend in the descriptor values, which parallels the trend in biological activity. In essence, all QSAR approaches imply, directly or indi-... 

Burden, F.R. and Winkler, D.A. 1999. New QSAR methods applied to structure-activity mapping and combinatorial chemistry. J. Chem. Inf. Corn-put. Sci. 39 236-242. 

R. S. Pearlman, in H. Kubinyi, ed., 3-D QSAR in Drug Design Theory, Methods and Applications, ESCOM Science Publishers, Leiden, the Netherlands,... 

An inexperienced user or sometimes even an avid practitioner of QSAR could be easily con-fiased by the multitude of methodologies and naming conventions used in QSAR studies. Two-dimensional (2D) and three-dimensional (3D) QSAR, variable selection and artificial neural network methods, comparative molecular field analysis (CoMFA), and binary QSAR present examples of various terms that may appear to describe totally independent approaches, which cannot be even compared to each other. In fact, any QSAR method can be generally defined as the application of mathematical and statistical methods to the problem of finding empirical relationships (QSARmod-els)of the form, D . D ), where... 

The seminal work of Corwin Hansch initiated the field of QSAR. Two-dimensional and three-dimensional QSAR methods (2-D QSAR and 3-D QSAR) have been widely applied to problems of biological interest. The latter approach has increased in popularity with the introduction of the comparative molecular field analysis (CoMFA) and commercial availability of similar methods. 

Evans, D.A., Doman, T.N., Thorner, D.A., and Bodkin, M.J. (2007) 3D QSAR methods phase and catalyst compared. Journal of Chemical Information and Modeling, 47, 1248-1257. 

Godha, K., Mori, I., Ohta, D. and Kikuchi, T. (2000) A CoMFA analysis with conformational propensity an attempt to analyze the SAR of a set of molecules with different conformational flexibihty using a 3D-QSAR method. /. Comput. Aid. Mol. Des.,... 

Xiao, Z., Varma, S., Xiao, Y.-D. andTropsha, A. (2004) Modeling of p38 mitogen-activated protein kinase inhibitors using the Catalyst HypoGen and k-nearest neighbor QSAR methods. J. Mol. Graph. Model, 23, 129-138. 

Xiao, Z., Xiao, Y.-D., Feng, J., Golbraikh, A., Tropsha, A. and Lee, K.-H. (2002) Antitumor agents. 213. Modeling of epipodophyllotoxin derivatives using variable selection k nearest neighbor QSAR method. J. Med. Chem., 45, 2294—2309. 

The carcinogenic potential of chemicals may be assessed by different types of (Q) SAR analysis which include (a) qualitative or semiquantitative SAR, (b) traditional QSAR analysis, (c) formalized computerized models or softwares, and (d) other methods snch as biologically based or molecular modelling methods [e.g., Rabinowitz et al. (2008)] or integrative methods. 

Ten years after the original CoMFA report [4], more than 100 CoMFA models have been reported on enzyme binding affinity and more than 100 on receptor binding affinity, respectively [31]. An alphabetical list of the 383 CoMFA papers published between 1993 and 1997 is available [83]. Over 200 papers illustrate the use of CoMFA and other 3D-QSAR methods in estimating AG d, with an average prediction error of 0.6-0.7 log units (0.85-1 kcal) for external sets of compounds [31]. This estimate, however, is unlikely to reflect the predictive power of CoMFA models for novel classes of compounds. Care needs to be exercised that the prediction step uses interpolation,... 

From the above, it can be concluded that while capturing similar information with respect to size, hydrophobicity, polarizability, and perhaps hydrogen bonding, the 2-D and 3-D descriptor systems are likely to differ significantly in the type of information that can be extracted from QSAR modeling. Since the information redundancy is under 40% overall, it is advisable to employ both 2D-QSAR and 3D-QSAR methods when modeling receptor-mediated target properties. This combination of QSAR methods is illustrated in the next section. 

D QSAR An extension of QSAR to 3-D properties of molecules. Initially, QSARs consisted of 1-D molecular descriptors only, although the method of... 

The first point especially addresses ecological considerations about the abundance and the distribution of sensitive species in the environmental compartment of concern the second aspect relates to the correct operation of QSAR methods. In the cases of the model contaminant phenol, which was chosen because of the availability of ample experimental data for the comparative exercise, sufficient knowledge is at hand to guide the retrieval of suitable QSARs. For toxicity to fish, the available models vary regarding (a) the endpoints measured - different fish species, different effects (NOEC, LC50, LCioo, ) different durations of the experiments (4 h-30 d), and (b) the various classes of chemicals studied. Because phenol is known to be a polar non-specific toxicant, suitable QSARs for fish (section 5.1) can be selected in a straightforward manner. These models are generally log P -dependent,... 

F. R. Burden and D. A. Winklei J. Chem. Inf. Comput. Sci., 39, 236 (1999). New QSAR Methods Applied to Structure-Activity Mapping and Combinatorial Chemistry. 

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