Steric misfit

A substitution of the methyl group in the para-position (Fig. 36) causes a larger expansion of the unit cell along c. The crystal packing of the resulting structure is still an efficient one, however the p-substituted methyl introduces already some steric hindrance into the structure the shortest distance of the methyl from its surroundings (adjacent phenyl walls ) is 3.56 A as compared to the normal van der Waals methyl — — phenyl distance of about 3.7 A49>. This steric misfit could be responsible for the preferential complexation of host 25 with m-cresol rather than with p-cresol. 

In real systems the formation of thermodynamically stable carbon structures having the minimum surface energy is inevitably accompanied by the separation of the elements that are excessive for some reasons due to chain breakage, energetic or steric misfit, etc. Besides, semiproducts that are readily soluble in benzene enter... 

In this way, MTD descriptors measuring the - steric misfit between the binding site cavity and the considered molecules are calculated as ... 

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. 

For a molecule coincident with the active region of the hypermolecule, it can be observed that c atoms are located at the hypermolecule cavity vertices (e = -1), and no atoms coincide with the hypermolecule wall vertices, i.e. there is no steric misfit and MTD = 0. 

MSDi is a descriptor of steric misfit defined as the number of unsuperposable nonhydrogen atoms for the maximal superimposition of the i th molecule to the reference molecule. MSD coincides with MTD when simple minimal steric differences are calculated with respect to the most active compound, no external atoms are considered in the hypermolecule, and the number of hypermolecule cavity vertices correspond to the atoms of the reference molecule. 

Differential descriptors such as -> steric misfit can also be considered as similarity/ diversity descriptors. 

The difference between the steric hindrance of the leading compound (assumed as the - reference compound) and the considered molecule. It is a measure of the similarity where low values of steric misfit correspond to high similarity between molecule and reference compound, i.e. a favourable condition for the considered molecule. 

Methods for evaluating the steric misfit are minimal topological difference and -+ molecular shape analysis. 

MSD is a descriptor of steric misfit defined as the number of nonoverlapping nonhydrogen atoms for the maximal superimposition of the ith molecule to the reference molecule. 

During the optimization process, the vertices of H are assigned to the receptor cavity, to the receptor walls or to the exterior of cavity that is the so-called steric irrelevant zone. The degree of steric misfit for the molecule Mj, i.e. the value of MTDi, is defined as the sum of the number of cavity vertices in H unoccupied by Mi and the number of waU vertices in H occupied by Mi. The whole number of H (meaning cavity, wall and irrelevant zraie) obtained by the optimization procedure makes up a hypothetical steric receptor map. Really, the optimization procedure is a mapping of a receptor space by means of regression analysis (Simon et al. 1978,1984 Ciubotariu et al. 2001a, b). 

MCD is a 3D-measure of steric misfit between the most active compound and the others within a given series of ligands under study. It translates the topological similarity/dissimilarity MSD parameter, which is an extended Hamming distance, from 2D space into a 3D space (Ciubotariu et al. 1990). 

The steric misfit of molecule is measured by MTDi, calculated with relation (15.36). If a molecule M has several low energy conformations, it will adopt the one which best fits to the receptor site. This is the conformation k of Lj with the lowest MTDik value. 

MTD, another early 3D-QSAR method, also quantitates the degree of steric misfit between the molecule and the receptor binding site. The MTD of a molecule is calculated by comparing it to a reference hypermolecule that contains all positions occupied by any of the molecules of the training set. As with MSA parameters, typically MTD is included in a regression equation with other physical properties. Activity is expected to decrease linearly with MTD. 

The work described here consists of two types of approaches to the steric fit problem, The first approach consists of developing new parameters to describe different characteristics of the molecular shape Ci.e, branching, bulkiness) this is done by means of topological indices. The second approach is based on minimal steric differences, a measure for steric misfit which depends not only on molecular shape,but also on the receptor and allows a guess of the shape of the receptor cavity. Brief reviews will be given on other steric parameters which will often be compared, in QSAR s, with parameters developed by the authors of these Lecture Notes, Electronic parameters and hydrophobi-city-intermolecular force parameters, to be used together with steric parameters in OSAR s, are also briefly discussed. Other items include the metric introduced by minimal steric difference and computer programs developed in connection with our steric parameters. 

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