Steric descriptors

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. 

Bowden-Wooldridge steric constant -> steric descriptors (O number of atoms in substituent specific positions)... 

Bowden-Young steric constant steric descriptors (O Charton steric constant) branching index Randic connectivity index - connectivity indices branching layer matrix layer matrices... 

Dubois steric constant - steric descriptors (O Taft steric constant) dummy variables indicator variabies... 

F strain substituent front strain -> steric descriptors... 

Jenkins steric parameter -> steric descriptors Jt index -> Balaban distance connectivity indices J/J index -> bond order indices (O graphical bond order)... 

Usually hydrophobicity is encoded by - steric descriptors such as molar or - molecular volume which account satisfactorily for nonpolar interactions polarity can be described by polar terms which are negatively related to lipophilicity. An important factorization of lipophilicity is provided by the - solvatochromic parameters. Moreover, a measure of the global polarity of a given solute was proposed by Testa and coworkers [Testa and Seiler, 1981 El Tayar and Testa, 1993 Vallat et al., 1995] and called the interactive polar parameter A (or the Testa lipophobic constant). It is defined as the difference between the experimentally measured lipophilicity and that estimated for a hypothetical n-alkane of the same molecular volume V as ... 

There are several methods developed for the calculation of logP from molecular structure, based on -> substituent constants, - fragmental constants, - electronic descriptors, -> steric descriptors, - connectivity indices, surface areas, - volume descriptors, and -> chromatographic descriptors [Leo, 1990 Hansch et al., 1995b Carrupt et al., 1997 Reinhard and Drefahl, 1999]. 

The MTDi descriptor is a measure of steric misfit of the ith molecule with respect to the receptor cavity and is equal to the number of unoccupied cavity vertices plus the number of occupied wall vertices it can be considered among both - steric descriptors and - differential descriptors. 

When molar refractivity is determined using the sodium D-line, it coincides with the - electron polarization P. Therefore, it can be considered contemporarily as being among - electronic descriptors as well as - steric descriptors. 

The three-dimensional representation views a molecule as a rigid geometrical object in space and allows a representation not only of the nature and connectivity of the atoms, but also the overall spatial configuration of the molecule. This representation of a molecule is called geometrical representation, and molecular descriptors derived from this representation are called 3D-descriptors. Examples of 3D-descrip-tors are -> geometrical descriptors, several -> steric descriptors, and -+ size descriptors. 

Molecular descriptors are usually classified into several classes by a mixed taxonomy based on different points of view. For example, descriptors are often distinguished by their physico-chemical meaning such as - electronic descriptors, - steric descriptors, lipophilicity descriptors, -> hydrogen-bonding descriptors, - shape descriptors, charge descriptors, - electric polarization descriptors, - reactivity descriptors, moreover, on the basis of the specific mathematical tool used for the calculation of the molecular descriptors, - autocorrelation descriptors, -> eigenvalue-based descriptors, -> determinant-based descriptors, - Wiener-type indices, - Schultz-type indices can be distinguished. 

Besides substituent constants, the descriptors used in the OASIS approach are - topological indices, - geometrical descriptors, - steric descriptors, and -> electronic descriptors, both for molecules and their fragments. 

Substituent front strain, steric energy difference, - Joshi steric descriptor and - Joshi electronic descriptors are examples of molecular descriptors calculated from the standard enthalpy of formation and the steric energy. 

Molecular descriptors related to the dimensions of the molecule and often calculated from the - molecular geometry. Combined with molecular shape information, they are closely related to - steric descriptors. The simplest size descriptors are atom count, -> bond count, -> molecular weight, and some among the -> volume descriptors such as van der Waals volume. Other size descriptors are - Sterimol parameters and - WHIM size descriptors. 

Steric descriptors account for both the size and shape of molecules and substituents, and are thus contemporarily related to -> size descriptors and - shape descriptors. However, in several QSAR models, size descriptors are encountered as estimates of steric molecular/fragment properties. 

The term bulk descriptors can be used to denote steric descriptors of the whole molecule, referring to the measure of the hindrance of the molecule when it is considered as a part of a system and dense assembly, each molecule being constrained by its neighbours to a limited region in space. 

Steric descriptors were obtained from -> experimental measurements of equilibrium and rate constants, - computational chemistry, geometrical and structural characteristics, and the - topological representation of a molecule. 

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. 

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