Steric CoMFA

Fig. 5 Example of steric CoMFA contour map results using APO (2-amino-3H-phenoxazin-3-one) for visualization near green area greater toxicity is correlated with more bulky groups and near yellow area with the less bulky group. 

Table 3 Overlap of the CoMFA Steric, CoMFA Electrostatic, and HINT stdev P Fields and the Binding Site Structure" ...

In the case of aromatase inhibition, the overlap of steric CoMFA fields with other external, potent, aromatase inhibitors allowed us to hypothesize the existence of two different, hydrophobic binding pockets a small one, favoring mostly steric interactions, but limited in tolerance (6p-ethyl was optimal), and a large one, tolerant to aromatic substituents, both located in the vicinity of the carbon at the 6 position (see Figure 5). 

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. 

To refine this model qualitatively, the binding of several of these compounds was subjected to a CoMFA (Comparative Molecular Field Analysis) [39], This program examines electrostatic and steric parameters... 

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

The classical CoMFA procedure relies on sterical and electrostatic fields or on spatial interaction energy maps of the potential ligands with standardized hydrophobic or polar probe molecules [56]. In this work, the modified ComPharm approach described in detail elsewhere [25] will be used. Its key differences with respect to classical CoMFA are the following ... 

More recently, with the significant increases in computer power even on desktop PCs, methods for directly matching 3-D features of molecules have become more prevalent. Features here generally refer to various types of molecular fields, some such as electron density ( steric ) and electrostatic-potential fields are derived from fundamental physics (30,31) while others such as lipophilic potential fields (32) are constructed in an ad hoc manner. Molecular fields are typically represented as continuous functions. Discrete fields have also been used (33) albeit somewhat less frequently except in the case of the many CoMFA-based studies (34). 

CoMFA is based on interactions between a molecule and a probe traditionally, the probe has the properties consistent with a van der Waals sp3 carbon and a charge of +1.0. The interactions calculated between the probe and the molecules of interest are steric (van der Waals 6-12) and electrostatic (Coulombic with a 1/r dielectric) energies (4). The CoMFA process starts by constructing a 3D grid... 

Another class of 3D descriptors is molecular interaction field (MIF) descriptors, with its well-known example of Comparative Molecular Field Analysis (204,205) (CoMFA). In CoMFA, the steric and electrostatic fields are calculated for each molecule by interaction with a probe atom at a series of grid points surrounding the aligned molecules in 3D space. These interaction energy fields are correlated with the property of interest. The 3D nature of the CoMFA technique provides a convenient tool for visualization of the significant features of the resulting models. 

Waller et al. (237) performed a CoMFA study to analyze the metabolic rates of CYP2E1 in rodents as intrinsic clearance of a 12 chlorinated volatile organic compounds (VOCs). After superimposition, the steric and electrostatic field interaction energies, the HINT (/jydropathic interactions) energy (238), and molecular orbital field were calculated in addition to clogP. The best model... 

We have shown the contours for standard (Figure 9.10) and dock (Figure 9.11) databases. A comparison of these contour plots is meaningful. Without any information regarding the possible involvement of hemin in the MOA, the standard CoMFA contour plots reveal a large red (sterically forbidden) plate-shaped contour on the peroxy face of artemisinin. In this instance, the side chains project in any favorable minima, including the area occupied by hemin. Likewise, smaller green contours are positioned about C-9 and C-3 and the "equator" of the molecule. In contrast, the dock database shows attenuated red contours in the... 

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