Steric field, CoMFA

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. 

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. 

Comparative molecular field analysis (CoMFA) is comprised of relating measurements of the electrostatic and steric fields around a template molecule to the molecule s biological activity. The CoMFA methodology is based on the assump-... 

Molecules are characterized by potential hydrogen bonding, polar, hydrophobic, and electrostatic interactions in 3D space, using 3D molecular fields. Techniques such as Comparative Molecular Field Analysis (CoMFA), which considers the 3D distribution of electrostatic and steric fields, have been applied to congeneric series of enzyme substrates or inhibitors generating 3D QSAR equations. Most examples of such applications are to modeling CYP substrate and inhibitor specificity and these have been extensively reviewed in the literature (Ekins et al., 2000 2001 Ter Laak and Vermeulen, 2001 Ter Laak et al., 2002). 

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... 

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. 

Sulea, T, Oprea, T.I., Muresan, S. and Chan, S.L. (1997). A Different Method for Steric Field Evaluation in CoMFA Improves Model Robustness. J.Chem.Inf.Comput.Sci., 37,1162-1170. 

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. 

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... 

Fig. 5 CoMFA overlays for KMO inhibitors, Green and yellow - Steric fields. Green areas show where bulk is favorable yellow areas indicate green) where bulk is unfavorable. Blue and red -electrostatic fields. Red areas show are favorable for negative charge, i.e., oxygens, whereas blue are areas unfavorable for negative charge...

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 15 Comparison of stdev coeff CoMFA fields for CoMFA models derived on 5-HTia activity (compound numbers as in Fig. 12). Electrostatic fields are on the left, steric fields on the right. (See color plate at end of chapter.)...

Sulea T, Oprea TI, Muresan S, Chan SL. A different method for steric field evaluation in CoMFA improves model robustness. J Chem Inf Comput Sci 1997 37 1162-1170. 

We generated a CoMFA fit of the erythromycin esters, adding the substituents to the crystal structure of the unsubstituted compound. Only steric fields were significant. Table 3.5 (below) summarizes the statistics. 

CoMFA and related 3D QSAR approaches have been applied to correlate various physicochemical properties. Equilibrium constants of the hydration of carbonyl groups could be explained by a combination of C=0 bond order, steric, and electrostatic fields [1005]. 3D QSAR studies that correlate a, inductive, and resonance parameters of benzoic acids [1015, 1016] as well as pKg values ofclonidine analogs [1017] show that a H " field precisely describes such electronic parameters, e.g. (Jm.p of benzoic acids (n = 49 rpir = 0.976 snr = 0.082 Spress = 0.093). Steric parameters of benzoic acids, like surface area and van der Waals volume can be described by a steric field alone, while values of acetic acid methyl esters need a combination of both steric and electrostatic fields (n = 21 rpix = 0.984 Sfit = 0.133 SpREss = 0.209) [1016]. 

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