Comparative Molecular Field Analysis method

As in the case of other CSPs, the chiral resolution is effected by the structure of the solute. The chiral resolution of amino acids may be considered as the best example for this study. The work of Fukushima et al. [20] (i.e., the chiral resolution of amino acids) indicated the different behavior of the chiral resolution on (i8 )-/V-3,5-dinitrobcnzoyl-l -naphthylglycine CSP. Altomare etal. [142] studied the chiral resolution of a series of 3-phenyl-4-(l-adamantyl)-5-A-phcnyl-A2-1,2,4-oxadiazolines on A,Af,-(3,5-dinitrobenzoyl)-l(7 ),2( )-diaminocyclohcxanc CSP. The effect of the influence of aromatic ring substituents on enantioselectivity was studied by traditional linear free-energy-related equations and comparative molecular field analysis methods. The authors reported that an increase in retention was favored by the re-basicity and the hydrophilicity of the solutes. In... 

The SYBYL molecular modeling package is known for having the comparative molecular field analysis method for finding three-dimensional QSAR. 2 CJACS hits for CoMFA (Comparative Molecular Field Analysis) are plotted in Figure 20. CoMFA was mentioned in the CJACS database 9% as often as SYBYL, indicating that SYBYL is being used for many functions other than CoMFA. 

Langlois, M., Bremont, B., Rousselle, D. and Gaudy, F. (1993a). Structural Analysis by the Comparative Molecular Field Analysis Method of the Affinity of Beta Adrenoceptor Blocking Agents for 5-HtlA and 5-HtlB Receptors. Eur.J.Pharmacol, 244,77-87. 

Spherical harmonics provide a parameterization of three-dimensional shape which is especially useful for protein structure description (4). Overlap volume comparisons are the basis for the Molecular Shape Analysis (MSA) method of Hopfinger (5,6). TTiis technique has been extended to include a quantification of the steric and electrostatic fields surrounding a molecule (7). A further refinement of field analysis, which merges statistical and molecular modeling techniques, is the COMparative Molecular Field Analysis method (COMFA) of Cramer (8). These latter approaches seek to encode information about more than just steric bulk or form. They express multivariate information about the structure, so they might be considered multidimensional shape descriptors. 

After an alignment of a set of molecules known to bind to the same receptor a comparative molecular field analysis CoMFA) makes it possible to determine and visuahze molecular interaction regions involved in hgand-receptor binding [51]. Further on, statistical methods such as partial least squares regression PLS) are applied to search for a correlation between CoMFA descriptors and biological activity. The CoMFA descriptors have been one of the most widely used set of descriptors. However, their apex has been reached. 

Cho SJ, Tropsha A. Cross-validated R2-Guided region selection for comparative molecular field analysis a simple method to achieve consistent results. I Med Chem 1995 38(7) 1060-6. 

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... 

Partial Least Squares (PLS) regression (Section 35.7) is one of the more recent advances in QSAR which has led to the now widely accepted method of Comparative Molecular Field Analysis (CoMFA). This method makes use of local physicochemical properties such as charge, potential and steric fields that can be determined on a three-dimensional grid that is laid over the chemical stmctures. The determination of steric conformation, by means of X-ray crystallography or NMR spectroscopy, and the quantum mechanical calculation of charge and potential fields are now performed routinely on medium-sized molecules [10]. Modem optimization and prediction techniques such as neural networks (Chapter 44) also have found their way into QSAR. 

From comparative molecular field analysis (COMFA)5. This method can be used for electrical, steric and polarizability parameters. 

Cruciani, G. and Watson, K.A. Comparative molecular field analysis using GRID force-field and GOLPE variable selection methods in a study of inhibitors of glycogen phosphorylase b. 

The popularity of commercial programs such as Comparative Molecular Field Analysis (4,12) (CoMFA) and Catalyst (13) has limited both the evaluation and use of other QSAR methodologies. Often well-known issues associated with CoMFA and Catalyst have come to be viewed as shortcomings that simply are accepted as working limitations in a 3D-QSAR analysis. In this section we challenge this position and present 3D- and nD-QSAR methods that are able to overcome some of the issues associated with current mainstream 3D-QSAR application products. 

The QSAR package Comparative Molecular Field Analysis (CoMFA) (4) is a method allowing the exploration of a molecule s physical properties similar to how the active site would feel the molecule (85). CoMFA possesses four essential parts ... 

Collective coordinates, 35, 98 Collision theory, 528, 542 Comparative molecular field analysis, 308-310 Complete basis set, see Multilevel methods) Compressibility, 418, 446 Condensed-phase effects, see also Solvation... 

The criticisms in the previous paragraphs lead to a question If Hansch analysis is of such questionable value, then why has an entire chapter of this textbook been devoted to the subject Despite the fading utility of classical QSAR methods such as Hansch analysis, the logic behind Hansch analysis is invaluable to medicinal chemistry. Synthetic chemists in the pharmaceutical industry intuitively consider the ideas used to construct Hansch equations. Ideas such as electronics, sterics, and lipophilicity underlie traditional SAR approaches in the laboratory. Critical analysis of activity data and emphasis on seeking holes in R-group selection are also fundamental to successful SAR on a lead. Through the study of Hansch analysis, all these crucial ideas are presented in a rational framework that helps demonstrate their relevance. Just as importantly, Hansch analysis provides the foundation for the next generation of QSAR comparative molecular field analysis. 

Comparative molecular field analysis (CoMFA) is a modern, powerful extension of the classical QSAR methods that were developed in the 1960s.14 While Hansch analysis is simple to understand and fairly easy for any medicinal chemist to perform, CoMFA requires specialized software and an understanding of statistics. Since CoMFA is outside the experience of most synthetic chemists, pharmaceutical companies have dedicated computational chemistry groups to handle advanced QSAR tasks. 

Cmciani, G., Watson, K. Comparative Molecular Field Analysis Using GRID Force Field and GOLPE Variable Selection Methods in a Study of Inhibitors of... 

However, it is normally assumed that the conformers that bind to target sites will be those with a minimum potential energy. Since molecules may have large numbers of such metastable conformers a number of techniques, such as the Metropolis Monte Carlo method and comparative molecular field analysis (CoMFA), have been developed to determine the effect of conformational changes on the effectiveness of docking procedures. 

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