CoMFA electrostatic field

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 ... 

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... 

Moreover, a final 3D-QSAR model vahdation was done using a prospective study with an external test set. The 82 compounds from the data set were used in a lead optimization project. A CoMFA model gave an (cross validated) value of 0.698 for four relevant PLS components and a conventional of 0.938 were obtained for those 82 compounds. The steric descriptors contributed 54% to the total variance, whereas the electrostatic field explained 46%. The CoMSIA model led to an (cross vahdated) value of 0.660 for five PLS components and a conventional of 0.933. The contributions for steric, electrostatic, and hydrophobic fields were 25, 44, and 31%. As a result, it was proved that the basic S4-directed substituents should be replaced against more hydrophobic building blocks to improve pharmacokinetic properties. The structural and chemical interpretation of CoMFA and CoMSIA contour maps directly pointed to those regions in the Factor Xa binding site, where steric, electronic, or hydrophobic effects play a dominant role in ligand-receptor interactions. 

From the studies above, it was shown that the use of 3D-QSAR models led to the identification of binding site regions, where steric, electronic, or hydrophobic effects played a dominant role. Although cationic interactions in both SI and S4 subsites were favorable for in vitro affinity, they might be detrimental for oral bio availability. Thus, the CoMFA steric field contribution could be seen as a balance between pure steric plus hydrophobic effects. The contributions for steric, electrostatic and hydrophobic fields from the CoM-SIA studies were 25, 44, and 31%, respectively. 

The CoMFA model obtained with only the steric field showed (cross-validated) = 0.520 from nine components, (non cross-validated) = 0.969, F value = 55.811, = 0.985, while the model with only the electrostatic field... 

The foundation of the CoMFA approach lies in the fact that the interaction between the biotarget and organic ligand is usually non-covalent and substantially controlled by the shape of molecules. In addition, van der Waals and Coulomb forces in most cases provide an adequate description of non-covalent interactions within a molecular mechanics framework. Thus, the authors assumed that the biological action of compounds can be explained by the shape and electrostatic field of their molecules. 

In recent years, three-dimensional quantitative structure biological activity relationship methods known as comparative molecular field analysis (CoMFA) has been applied to construct a 3D-QSRR model for prediction of retention data. The CoMFA 3D-QSRR model is obtained by systematically sampling the steric and electrostatic fields surrounding a set of analyte molecules. Next, the differences in these fields are correlated to the corresponding differences in retention. The CoMFA model was successfully applied to HPLC retention data of polycyclic aromatic hydrocarbons [60]. 

Depending on the selected probe and the defined potential energy function, several molecular interaction fields can be calculated. The most common are steric fields and electrostatic fields, sometimes referred as CoMFA fields because originally implemented in CoMFA. Several interaction fields are actually calculated in the - GRID method. 

Durst, G.L. (1998). Comparative Molecular-Field Analysis (CoMFA) of Herbicidal Protoporphyrinogen Oxidase-Inhibitors Using Standard Steric and Electrostatic Fields and an Alternative LUMO Field. Quant.Struct.-Act.Relat., 17,419-426. 

The group of Lipkowitz et al. also performed computational studies of chiral catalysts using COMFA of an asymmetric Diels-Alder reaction with catalysts containing bisoxazoline or phospinooxazoline ligands that are known to induce asymmetry [20]. Approximately 70% of the variance in the observed enantiomeric excess can be attributed to the sterical field and the remainder of the variance to the electrostatic field. 

The statistics and the isocontour maps of our preliminary CoMFA model are shown in Figure 4. It can be seen that both steric and electrostatic fields contribute to the model and, within the limits of the physicochemical domain explored, the former is prevalent. 

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