CoMFA method

The biggest limitation of the CoMFA method is the alignment step. The algorithm superimposes the portions of the inhibitors that are of similar stmcture, assuming that they bind with similar orientations in the active site of the enzyme, which is not necessarily the case. Also, because of a problem with alignment, a CoMFA may fail when a few molecules are very dissimilar from all others in the series. Like QSAR, CoMFA does not require a stmcture of the relevant biological receptor, but does require knowledge about a series of inhibitory compounds. 

Agarwal, A., Pearson, P. P., Taylor, E. W., Li, H. B., Dahlgren, T., Herslof, M., et al. Three-Dimensional Quantitative Structure-Activity Relationships of 5-HT Receptor Binding Data for Telrahydropyridinyl Derivatives A Comparison of the Hansch and CoMFA Methods../. Med. Chem. 1993,36, 4006-4014. 

The GRID program [44] has been used by a number of workers as an alternative to the original CoMFA method for calculating interaction fields. An advantage of the GRID approach, apart from the large number of chemical probes... 

More complex ways exist, which offer powerful capabilities, and are useful in certain situations. CoMFA methods, for instance, overlap a series of structures on the basis of a common molecular moiety. The differences in the electrostatic and sterical behavior are then assessed in relationship to the property to be modeled [10]. 

The initial drive of Tripos s [68] first products in this field seemed to be towards the analysis, design and management of large, generally diverse libraries. The company have also been active in deriving new descriptors (section 2.3.1), and in trying to determine and validate a best set of descriptors to describe absolute diversity [69]. Modules are available for deriving SARs (particularly the CoMFA method), so the basic tools for... 

The next step was made by Klebe et al. [50]. Two 3D-QSAR methods were applied to get three-dimensional quantitative structure-activity relationships using a training set of 72 inhibitors of the benzamidine type with respect to their binding affinities toward Factor Xa to yield statistically reliable models of good predictive power [51-54] the widely used CoMFA method (for steric and electrostatic properties) and the comparative molecular similarity index analysis (CoMSlA) method (for steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor properties). These methods allowed the consideration of various physicochemical properties, and the resulting contribution maps could be intuitively interpreted. 

The method of Molecular Field Topology Analysis is one of the hyperstucture-based QSAR techniques. It was proposed as a topological analogue of the CoMFA method because it is based on topological rather than spatial cilignment of structures [Zefirov et al, 1997a Palyulin et al, 2000]. 

Carrieri, A., Altomare, C, Barreca, M.L., Contento, A., Carotti, A. and Hansch, C. (1994). Papain Catalyzed Hydrolysis of Aryl Esters A Comparison of the Hansch, Docking and CoMFA Methods. II Farmaco, 49,573-585. 

Oprea, T.I., Ciubotariu, D., Sulea, T. and Simon, Z. (1993). Comparison of the Minimal Steric Difference (MTD) and Comparative Molecular Field Analysis (CoMFA) Methods for Analysis of Binding of Steroids to Carrier Proteins. Quant.Struct.-Act.Relat., 12,21-26. 

In the original CoMFA method only two fields of noncovalent ligand-receptor interactions were calculated the steric field that is a Lennard-Jones 6-12 potential function and the electrostatic field that is a Goulomb potential energy function. Usually, the two fields are kept separate to facilitate the interpretation of the final results. As steric and electrostatic... 

Elass, A., Brocard, J., Surpateanu, G. and Vergoten, G. (1999) Conformational searching using the comparative molecular field analysis (CoMFA) method of substituted arene-tricarbonyl-chromium complexes./. Mol. Struct. (Theochem), 466, 21-33. 

Steric fields derived from the CoMFA method [75] were used as 3D shape descriptors, while their major drawback is that a reliable superposition rule for databases is required. Thus, topomeric fields as significant enhancement for comparing the diversity of a set of variable groups attached to a common scaffold have been developed and validated [76], Those fields rely on canonical conformations of aligned compounds from combinatorial libraries using the reaction core. They use a novel way to encode flexibility depending on the shortest bond distance between any atom to the reaction core. 

Figure 6 An overview of the CoMFA method. See text for details. (Modified from Cramer et al. [4].)...

Oprea TI, Ciubotariu D, Sulea T, Simon Z. Comparison of the minimal steric difference (MTD) and comparative molecular field analysis (CoMFA) methods for analysis of binding of steroids to carrier proteins. Quant Struct-Act Relat 1993 12 21-26. 

Several studies on data sets of considerable size, mainly utilizing the CoMFA method [113], were conducted by the group of Avery [106-109]. 

In the CoMFA method developed by Cramer et a molecule is described using electrostatic, steric, and, sometimes, hydrogen bonding fields calculated at the... 

A number of questions remain open, including extension of the present approach to objects in 3D space. Are the binary shape codes sufficiently general, i.e., can they be extended to 3D structures We cannot answer these questions since they have not yet been considered. We will, however, outline briefly an approach to the 3D case. A generalization from planar contours to surfaces in a 3D space is possible even if not unique. For example, we first derive for a 3D surface a set of 2D contours. Such are, for example, the electrostatic maps that have found use in QSAR in the well-known CoMFA method. Once we have the contours, each contour can be encoded by the binary code as illustrated in this chapter. A list of such contours, with specifications of their relative positions, will lead to a 3D code for molecular shapes. Comparisons of 3D shapes will now be more involved. 

Since drugs and their targets are three-dimensional objects, it is of course appropriate to consider 3D molecular propeities. This is the objective of several approaches, combining statistical and modelling techniques, referred to as 3D-QSAR. The comparative molecular field analysis (CoMFA) method has been widely used and will be discussed elsewhere in this book (see Chapter 25). 

Figure 54 The CoMFA method. Field calculation in a grid and generation of the QSAR table for PLS analysis (reproduced from Figure 1 of ref. [36) with permission from the American Chemical Society, Washington, DC, USA).

The use of additional (or other) fields than the default steric and electronic fields of the original CoMFA method, together with PLS analysis or GOLPE, is quite common as a valuable extension of the CoMFA program, but it also constitutes an alternative to the relatively expensive commercial software. A combination of shape, lipophilic, steric, and electrostatic potentials in comparative analyses was termed comparative molecular potential analysis (CoMPA) [1014],... 

However, despite the simplicity of the analyses and the good correlations obtained in these studies, a ligand interaction-based model like the CoMFA method should not be used to model nonlinear effects arising from transport and distribution no reasonable results can be expected for sets of compounds which are no homologous series. Better and theoretically more consistent alternatives would be the addition of suitably weighted log P values to the CoMFA table, the use of lipophilicity similarity matrices (chapter 9.4), or the correlation with log P values in the classical manner, applying either the parabolic or the bilinear model. 

Tel. 804-786-8490, fax 804-371-7625, e-mail dabraham ruby.vcu.edu Hydrophobic field for use with CoMFA method in SYBYL. VAX, Silicon Graphics and Evans 8c Sutherland ESV workstations. 

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