Electrostatic CoMFA

TV =48), and a seven-PLS-component model was reported for arAR, with a 0.6 contribution from electrostatic fields (N = 42). This difference can be traced back to the 10 compounds removed from the initial data set while using the MCS alignment, but the models were perhaps overfitted in this particular case. We further notice that the electrostatic CoMFA field contributions (Table 5), 0.63 for 5HT1A, and 0.66 for arAR, respectively, are in qualitative agreement with the previously reported higher component models [128]. Based on the comparative QSAR approach, the two- or three-PLS component models are warranted for both 5HT1A and arAR in this data set. 

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... 

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... 

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