Molecular steric fields

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. 

Within the MM2 force field, the molecular steric energy is given by... 

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

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... 

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 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. 

In - grid-based QSAR techniques, the energy value at each grid point p constitutes a molecular descriptor. For the selected -> molecular interaction fields (steric, hydrophobic, coulombic, etc.), the calculated value at each grid point p depends on the relative orientation of the compound with respect to the grid. As a consequence, the use of... 

Buckingham potential function - molecular interaction fields (O steric interaction fields)... 

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. 

The most common steric descriptors are - molar refractivity, -> surface areas and several - volume descriptors such as molecular volume. Other steric descriptors are -> steric interaction fields, MTD descriptors, -> common overlap steric volume, and several topological descriptors accounting for both size and - molecular branching. Other popular molecular steric descriptors are listed below. 

The long awaited validation study for the XED method for molecular similarity has been published.69 Molecules are described using the maxima and minima in the electrostatic and steric fields around the molecule. These points form a pharmacophore, and so can be used to search databases for alternative chemotypes. As the representation is sparse, several conformations per molecule can be considered. A new chemotype with nanomolar potency for CCK2 and improved excretion properties was found. This is a good concrete example of the power of the XED representation. Other than that, this area has been comparatively quiet, awaiting more developments in alignment methods, as discussed in the next section (Table 1). 

Over the past years the search for more reliable discrimination of L/M relative steric size and theoretical prediction of the preferred interporphyrin helicity of the host—guest complex has led to the development of molecular mechanics calculations protocol using the Merck Molecular Force Field (MMFF) approach coupled to Monte Carlo-based conformational analysis.57... 

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