Steric field

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. 

SuLEA, T., Oprea, T.I., Muresan, S., and Chan, S.L. Different method for steric field evaluation in CoMEA improves model robustness./. Chem. Inf. Comput. Sci. 1997, 37, 1162-1170. 

D.E., and Ferguson, A.M. Bioisosterism as a molecular diversity descriptor steric fields of single topomeric conformers. 12... 

An alternative approach (30) treats the steric and electrostatic potential fields directly. The steric field is generally given by an expression similar to that in Eq. 2.70,... 

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). 

Moon, M. H., and Giddings, J. C. (1993). Rapid separation and measurement of particle size distribution of starch granules by sedimentation/steric field-flow fractionation./. Food Sci. 58 1166-1171. 

High-Speed Separation of Large ( > 1 /btm) Particles by Steric Field-Flow Fractionation, T. Koch and J. C. Giddings, Anal. Chem., 58, 994 (1986). 

Separation of Human and Animal Cells by Steric Field-Flow Fractionation, K. D. Caldwell, Z.-Q. Cheng, P. Hradecky, and J. C. Giddings, Cell Biophys., 6, 233... 

Williams PS, Moon MH, Giddings JC (1992) Fast separation and characterization of micron size particles by sedimentation/steric field-flow fractionation role of lift forces. In Stanley-Wood NG, Lines RW (eds) Particle size analysis. Royal Society of Chemistry, Cambridge, pp 280-289... 

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 adenosine A3 receptor antagonistic activity of these compounds have been further analyzed [104] in 3D-QSAR using molecular shape analysis (MSA) and molecular field analysis (MFA) techniques in Cerius2 (version 4.8) software [50]. hi this, Jurs atomic charge descriptors were used for the MSA study and H+ point charges and CH3 derived steric fields were used for the MFA study. In this 3D-QSAR study, MSA resulted in Eqs. 12 and 13 and MFA led to Eq. 14. 

Hoffstetter-Khun, S., T. Rosier, M. Ehrat, and H. M. Widmer, Characterization of yeast cultivations by steric field-flow fractionation, Anal. Biochem. 2 300-308 (1992). 

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. 

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